CHAIRPERSON
TALAMINI:I would like to call to order
this meeting of the Gastroenterology and Urology Devices Panel.

My
name is Dr. Mark Talamini.I am the
chairperson of the Gastroenterology and Urology Devices Panel.I am currently professor of surgery at the
Johns Hopkins University School of Medicine and Director of Minimally Invasive
Surgery there.

If
you haven't already done so, I would request that everyone in attendance at
this meeting sign in on the attendance sheet that is available on the table
outside the door.

At
this time I would like each panel member at the table to introduce him or
herself, state your specialty, position title, institution affiliation, and
status on the panel.And we'll start
over here on the right.

INTRODUCTIONS

MS.
BROGDON:Good morning.I'm Nancy Brogdon.I'm not a member of the panel.I'm the director of FDA's Division of Reproductive, Abdominal, and
Radiological Devices.

DR.
HOY:Chris Hoy, a clinical nephrologist
from upstate New York affiliated with the Rubin Dialysis Center.And we have a nocturnal program for seven
years.I'm a consultant.

DR.
LOCKRIDGE:Bob Lockridge.I'm a clinical nephrologist from Lynchburg,
Virginia.I started the first nightly
program in Lynchburg in '97.I've
trained over 57 patients and have over 159 hours of experience in nocturnal
patient care years.

DR.
MORAN:I'm John Moran.I'm a clinical nephrologist.I'm chief scientific officer at Satellite
Health Care in northern California and consulting professor at Stanford
University School of Medicine.I'm also
a panel member.

DR.
BLAGG:Chris Blagg.I'm emeritus executive director of the
Northwest Kidney Center in Seattle and professor of medicine emeritus,
University of Washington.And I've been
involved with home dialysis and nocturnal dialysis for more years than I like
to think.I'm a consultant.

DR.
GILLESPIE:I am Robert Gillespie.I'm a pediatric nephrologist from Corpus
Christi, Texas.I'm affiliated with
Driscoll Children's Hospital as well as an assistant professor of pediatrics at
Texas A&M University.

DR.
WEINGER:Matt Weinger.I'm a professor of anesthesiology,
biomedical informatics, and medical education at Vanderbilt University.And my area of expertise is in human factors
engineering and patient safety.And I'm
a consultant.

DR.
ARANOFF:I'm George Aranoff.I'm chief of the Nephrology Section and
professor at the University of Louisville.And I'm a consultant.

DR.
AFIFI:I'm Abdelmonem Afifi.I'm professor of biostatistics and former
Dean of the School of Public Health at UCLA.I'm a biostatistician.I'm a
panel member.

DR.
SADLER:I'm John Sadler.I'm a clinical nephrologist from Baltimore,
former head of nephrology at the University of Maryland.I've been involved in dialysis for more than
40 years now and formerly had the privilege of chairing this panel.

DR.
SCHULMAN:I'm Gerald Schulman.I'm a professor of medicine at Vanderbilt
University.I'm the director of
hemodialysis for the hospital.And I'm
a consultant.

DR.
DUFFELL:I'm Bill Duffell.I'm an industry rep for this panel.My graduate studies were in sciences and
pharmacology.

MS.
MOORE:I'm Christine Moore, retired
executive assistant and dean of students at the Baltimore City Community
College, consumer rep.

CHAIRPERSON
TALAMINI:Thank you very much.

I'll
now turn the meeting over to the executive secretary, Dr. Jeff Cooper, who
would like to make some introductory remarks.

DR.
COOPER:Good morning.I will now read the record of the conflict
of interest statement."The
following announcement addresses conflict of interest issues associated with
this meeting and is made a part of the record to preclude even the appearance
of an impropriety.

"To
determine if any conflict existed, the agency reviewed the submitted agenda for
this meeting and all financial interests reported by the committee
participants.

"The
conflict of interest statutes prohibit special government employees from
participating in matters that could affect their or their employers' financial
interests.However, the agency has
determined that participation of certain members and consultants, the need for
whose services outweighs the potential conflict of interest involved, is in the
best interest of the government.

"Waivers
have been granted for Drs. Christopher Blagg and John Moran for their interests
in firms that could be impacted by the panel's deliberation.Copies of these waivers may be obtained from
the agency's Freedom of Information Office, room 12A15 of the Parklawn
Building.

"We
would like to note for the record that the agency took into consideration
certain matters regarding Drs. John Sadler and Gerald Schulman.Each of these panelists reported current
and/or past interests in the firms at issue but in matters not related to
today's agenda.The agency has
determined, therefore, that they may participate fully in today's
deliberations.

"We
would also like to note for the record that the agency took into consideration
other matters regarding Drs. Robert Lockridge, Blagg, and Sadler.The panelists reported current and/or past
interests in firms at issue in matters related to today's discussion.Since the agenda item for this session
involves only particular matters of general applicability, the agency has
determined that these panelists may participate fully in the discussion.

"In
the event that the discussions involve any other products or firms not already
on the agenda for which an FDA participant has a financial interest, the
participant should excuse him or her self from such involvement.And the exclusion will be noted for the
record.

"With
respect to all other participants, we ask in the interest of fairness that all
persons making statements or presentations disclose any current or previous
financial involvement with any firm whose products they may wish to comment
upon.

"The
FDA seeks communication with industry and the clinical community in a number of
different ways.First, FDA welcomes and
encourages pre‑meetings with sponsors prior to all IDE and PMA
submissions.This affords the sponsor
an opportunity to discuss issues that could impact the review process.

"Second,
the FDA communicates through the use of guidance documents.Toward this end, FDA develops two types of
guidance documents for manufacturers to follow in submitting a pre‑market
application.One type is simply a
summary of the information that has historically been requested on devices that
are well‑understood in order to determine substantial equivalence.The second type of guidance document is one
that develops as we learn about new technology.FDA welcomes and encourages the panel and industry to provide
comments concerning our guidance documents.

"I
would also like to remind you that the tentative date for the last 2005
Gastroenterology and Urology Devices Panel meetings is scheduled for Friday,
October 21st, 2005.You may wish to
pencil in these dates on your calendars, but please recognize that this date is
tentative at this time.

"On
another note, information on purchasing transcripts or videos of today's
meeting can be found on the registration table, which is outside of the meeting
room."

Before
I turn the meeting back to Dr. Talamini, please ensure that all cell phones are
either turned off or placed in the silent ring mode so that they do not
interrupt the business of the meeting.

Dr.
Talamini will now continue.

CHAIRPERSON
TALAMINI:Thank you, Dr. Cooper.

Dr.
Susan Altaie of the Office of In Vitro Diagnostic Devices will now give a
presentation to the panel regarding the agency's critical path
initiatives.Dr. Altaie?

DR.
ALTAIE:Thank you and good morning.

FDA'S CRITICAL PATH
INITIATIVES, PRESENTATION

DR.
ALTAIE:I am the focal point for Center
for Devices under the critical path umbrella.And in my daytime job, I am Scientific Policy Adviser for the Office of
In Vitro Diagnostics.

Today
I will talk to you about what the critical path is, why is this an FDA
initiative, and what are the critical path tools that we speak about, what
projects we are pursuing at CDRH, and how you can get involved as an interested
individual.And then we can answer
questions if you have any.

Critical
path is a serious attempt to modernize the medical products' critical path and
market product development to make it more predictable and less costly.

If
you look at the critical path for device developments, you are looking at basic
research prototyping, preclinical, and clinical development, and then hopefully
FDA application and large production scales.

Well,
critical path will cover everything in that life cycle of development except
for the basic research.So one might
think why FDA gets involved in such a path.It's an industry job to develop.

Well,
because FDA believes in tremendous benefit of bringing innovative products to
the public faster.We also have a
unique perspective and understanding of product development.And we see the failures, the successes, and
the missed opportunities.And because
critical path will help us develop guidances and standards that foster
innovation and improve chances of success in the device development.

We
like to work together with companies and patient groups and academic
researchers and other stakeholders to modernize and develop and disseminate
tools that will help remove the science hurdles that affect product
development.

I
spoke about tools on the critical path.These are methods and techniques that work in three dimensions of
safety, efficacy, and industrialization of the devices.

Under
safety tools, those are the tools that will predict if potential products will
be harmful.And the efficacy tools will
determine if a potential product will have medical benefit and
industrialization tools.Those will
deal with how to manufacture a product at a commercial scale with consistently
high quality.

So
these tools that I describe in three dimensions, these are examples of
them.Biomarkers can be one of them by
Bayesian statistics, animal models of biomarkers, clinical trial design tools
and computer simulations, quality assessment, protocols, and post‑market
reporting.And we are also open to any
suggestions any of you have to add to this list of tools to follow up and ease
up the device development.

At
the CDRH, we deal with an array of devices, anywhere from Band‑Aids to
stethoscopes to CAT scans and heart valves and infusion pumps and glucose
monitoring devices.Everything that you
can think of medically are regulated under CDRH.And so there is a tremendous opportunity for developing tools to
get these devices faster to the market.

However,
I want to note that we at CDRH deal with devices that are totally different
than the drugs dealt with in CDER.Even
though we parallel in paradigm, the paradigms are different.We deal with complex components of the
devices, and we deal with biocompatibility.

We
have to have equipment that is durable and they long‑last.And then we also deal with devices that have
rapid cycle and turnover to the better model.We deal with malfunctions of instrumentation and user errors.And we study them by actually bench testing
them.

Our
regulations are different.We deal with
quality systems in ISO 9000, which is parallel but different than the GMPs that
CDER deals with.

These
are also areas of interest under the three dimensions that I spoke with you
about.The safety tools we are dealing
with biocompatibility databases, effects of products on disease or injured
tissue.When you look at the
effectiveness tools, you are talking about surrogate endpoints of cardiovascular
device trials, and you're talking about computers simulating modeling of the
implanted devices.

Under
the mass production, we are looking at the practice guidelines for follow‑up
of implanted devices.We are also
looking at validated training tools for devices with known learning curves by
the users.

These
are a few examples of critical path projects that we're pursuing in CDRH.Most of these are not funded.And we're trying to leverage funding from
outside stakeholders, whether it's industry or academia or government, other
government agencies.

We
are looking at developing a serum panel to assess sensitivity and specificity
of the hepatitis assays.We are looking
at computer models of human physiology to test and predict failures of
peripheral vascular stents before going into animals or human.

We
are looking at a clear regulatory path for intrapartum fetal diagnostic
devices.We are looking for consensus
from a safety community.And under the
surrogate markers, we are looking for pathways of statistical validations of
these markers.

We
are looking for development to develop practice guidelines for appropriate
monitoring of permanently implemented devices.And we also are looking for knowing the extent of the neurotoxicity
testing that is required in the tissue contacting, neural tissue contacting,
materials.

So,
as I said, these are the projects we have picked up with not having funding,
but all of these projects are in some steps of development and progress.If you are interested, you can participate
in two ways.You could give your views
and comments through the open public docket and tell us about areas that
benefit from research and development of critical path evaluative tools.

You
also can help us compile this national critical path opportunities list in the
areas that we have missed probably.And
there are ways to contact us.You could
go on the CDRH Web page under "News and Events," and you can go to
the links to the critical path white paper.And then there are links for the docket and the critical path group that
you could contact if you have any ideas.

I
would like to leave you with this thought that at CDRH, we work to ensure the
health of the public throughout the total product life cycle of the
products.And we believe it is
everyone's business.So I request your
involvement in critical path.

Any
questions?

(No
response.)

DR.
ALTAIE:All right.Thank you.

CHAIRPERSON
TALAMINI:Thank you, Dr. Altaie.

I
need to remind all of the panel members and speakers to talk directly into the
microphone when you talk for the transcriptionist's benefit.If they don't hear you, it's like you
haven't said it.Are you the
transcriptionist over there?Is that
person in the room?So if you aren't
getting something, raise your hand.And
I'll make sure that we have people speak clearly.

Next,
Dr. Susan Gardner of the Office of Surveillance and Biometrics will give a
presentation to the panel regarding the role of OSB in the review of post‑market
study designs.Dr. Gardner?

DR.
GARDNER:Thank you and good morning.

POST MARKET STUDY
DESIGN

DR.
GARDNER:I am going to spend a few
minutes this morning telling you about an important programmatic change in CDRH
and how that might impact you as panel members.

First
of all, the basis of the change is the move of the conditions of approval
program from the Office of Device Evaluation, ODE, to the Office of
Surveillance and Biometrics, which is the office which I'm the director of.

Briefly,
what we do in OSB is we are involved in pre‑market review by virtue of
the fact that we have the statisticians in OSB who are almost always involved
in PMAs, and we also have the epidemiologists in the office, who increasingly
are going to be involved in the PMA review process.

We
are responsible for adverse event signal detection.Again, we have the post‑market monitoring tools in the
office, including our medical device reporting program, our Medsun program, and
other surveillance tools.

We
are responsible for risk characterization.By that I mean the analysis of the post‑market data and
coordination of the center response for health care professionals when we see a
post‑market problem and we have a solution to get to.We are also responsible for interpreting the
medical device regulation.

For
condition of approval studies, the regulation tells us that in 21 CFR 814, post‑approval
requirements can include continuing evaluation and periodic reporting on the
safety, effectiveness, and reliability of the device for its intended use.Again, this is the basis for a condition of
approval studies program.

So
the impetus for change came from an internal study that we did a couple of
years ago.We looked at all of the PMAs
that were approved from 1998 to the year 2000.There were 127 PMAs.Forty‑five
of those were approved with condition of approval study orders.

So
we went back.Actually, the initial
effort was to go back and look at the quality of the condition of approval
studies, but we ran into a problem because we actually couldn't locate a lot of
these studies.It was a real red flag
for us.

We
found out that we had very limited procedures for tracking the progress and
results of these studies.There was no
automated tracking system or even manual tracking system in many cases.

We
also found, as you might expect, that many of the lead reviewers for these PMAs
had moved on to other jobs, either in the agency in a different division or
outside the agency.

Finally,
the folks in the pre‑market, particularly towards the end of an approval
process, are really heads down in improving the product, doing the labeling,
and all of the other things they need to do to get the product out the
door.And they really lack the
resources to focus on the condition of approval study.

So
we have a strategy for change.And
obviously the goal of the change is to obtain what is really critical post‑market
information as the device moves onto the market and to continue to assure the
safety and effectiveness of the device.And the important words, of course, are "in real world use."

The
device is moving from the tightly controlled clinical trials into community
use.And so it's really a critical time
to know what is going on if we have post‑market questions.

We
want to be able at that point to better characterize the risk‑benefit
profile of the device and, of course, to add to our scientific database so we
can make better decisions.

So
what did we do?Starting in January of
this year, we transferred the condition of approval program to OSB, although I
will say this was done after a two‑year pilot, where we tested some of
the procedures that I am going to tell you about.

We
have developed and instituted and is now up and running an automated tracking
system.So we're going to be able to
acknowledge the receipt of study reports and do follow‑up of reports if
they're not received.

We
have also added an epidemiologist to the PMA review team when it appears that
there is probably going to be a condition of approval study.The task of the epidemiologist is, first of
all, to think post‑market during the pre‑approval process.

So
during the approval process, their task with developing a post‑market
monitoring plan, it may or may not include a condition of approval study, but,
as I say, sort of when we think there is going to be one, that is when we will
have the epidemiologist on the team from the beginning.

The
epidemiologist will take the lead in developing.And, again, some key words here are "well‑formulated
post‑market questions," important questions.They are going to have the lead in the
design of the condition of approval study protocol.

And
they are going to be responsible for evaluating the study progress and the
results of the study once the product is approved.They will continue to work with the PMA team throughout this
process.It's just a matter of adding
their expertise to the team and changing the lead as the product goes to
market.

Why
do we think these changes will improve the program?Well, first of all, the development of important post‑market
questions and a good study design should be motivation both for FDA and for
industry to get these studies done.

We're
certainly willing to discuss the design of the studies throughout the conduct
of the studies.And if something
changes while the product is on the market, we are willing to make those
adjustments.Again, it's time, money,
and resources.And it's important that
we answer the important questions.

Second
of all, we're committed to acknowledging these studies when they come in to
CDRH and giving feedback on the studies.And, again, this is added motivation, both for the agency and for
industry to get these studies done.

We
will have a Web site, where we will post the status of the studies.So for folks who are doing them well, that
will show up.And if folks aren't doing
them well, that will also be on our Web site.And we do have the ability to mandate a post‑market study or order
a post‑market study if these studies are not being done.

So
what is the impact on the advisory panel?Post‑market questions come up often naturally during the
discussion of products as you are looking at them for approval.And sometimes we are going to have them come
up intentionally or pose post‑market questions during the process.And we are going to look to you.We want your advice, your suggestions on
possible approaches and any help that you can give us in thinking about what
the post‑market strategy might be.

During
the post‑market period, we're committed to having either FDA or industry
come back to the panel and give you an update on the progress and results of
the condition of approval studies for the approved devices.

Thanks.Do you have any questions?Yes?

DR.
DUFFELL:Will OSB be managing
registries as well as post‑market surveillance?

DR.
GARDNER:Yes.The condition of approval studies could have many possible
designs.And a registry is certainly
one design that could be part of the study.It would be managed somewhere else, but we would be part of looking at
the data and doing the analysis.

Yes?

DR.
MORAN:Would it be fair to say that
this might expedite the approval process if there are issues that you feel you
can deal with after approval, after marketing?

DR.
GARDNER:Well, certainly the pre‑market
requirements for safety and effectiveness don't change.But I think, again, thinking hard about what
our post‑approval questions are, thinking about what a good post‑approval
study design could be and how we could answer those questions are just going to
make us all feel more comfortable with the product.And knowing, again, that these studies are going to be done I
think, again, will add to our comfort level.

CHAIRPERSON
TALAMINI:Dr. Gardner, do you know
exactly ‑‑ this is Talamini here ‑‑ what percentage of
post‑market studies were completed out of that number?

DR.
GARDNER:Well, I don't.We had a number that we were using because
it was the number that we could find and the ones that were not accounted for.

What
we did not do was to go back to industry and call them up and say, you know,
"We don't have your post‑market study.Did you do it or did you not?"It's not a place we would have liked to have been, but just
because for resource issues, we made the decision to move forward, rather than
to go back.

The
products, again, were approved between 1998 and 2000.So if the studies weren't done, these were products that we had
been looking at for a number of years.So it wasn't clear, again, sort of a resource issue, that going
backwards would have been as beneficial as going forward in this case.

CHAIRPERSON
TALAMINI:Any other questions for Dr.
Gardner?Yes?

DR.
AFIFI:I appreciate the increased role
for an epidemiologist in post‑market studies because of their expertise
in data collection and so on.My
question is regarding the analysis.How
will that be coordinated between the epidemiologist and the statisticians?

DR.
GARDNER:Well, mostly the analysis
should be done by the companies.What
they send us is a report, similar to what is sort of done now.They're conducting the study.They should collect the data.They should do the analysis.

The
data will come in to us.We will review
it.If we have any questions, we get to
go back to the company and ask them to provide additional information.But the epi person will take the lead in
doing the analysis, but they will share this with people who were members of
the PMA approval team.So that they
will also have input into the condition of approval study.

DR. SADLER:You said these things will be posted on the Web site.And obviously a good posting will be the
carrot for the company ‑‑

DR.
GARDNER:Yes.

DR.
SADLER:‑‑ to encourage
them to get the studies done, for which I am very happy to hear.You also said that there might be penalties
and other studies if they were not completed.Could you go a little further on the penalties?Who would design subsequent post‑marketing
studies?

DR.
GARDNER:Yes.We have a regulation.Well, actually, the law says that we are allowed to impose post‑market
studies for various reasons.And
essentially the easy way to say it is if we have a major post‑market
question, then we think that there might be a danger to the people using the
device.

So
if we have a well‑formulated post‑market question for the condition
of approval studies that has not been answered, that will translate very well
into this requirement that we have to do this post‑market study.It's called section 522.

So
when we do this, we go to the company.And we tell them what our question is.It is their job to go back and design a study and come back to us and
say, "This is what we are proposing."

Now,
if we have gotten to this point with the company, obviously we're running into
a lot of problems.But at that point if
they are still not doing it, we can impose civil money penalties and the
product can be labeled as misbranded.

DR.
SADLER:Okay.Would you expect to consult with the advisory panel members or
with some of them in reviewing these subsequent studies?

DR.
GARDNER:I think it is entirely
possible.I mean, we have an appeals
process.And, again, if we are sort of
to the point where we are ordering a secondary study because the condition of
approval study hasn't been done, there's a message here about some real
conflict between industry and FDA.

So
we would go up through the appeal process.That would also include perhaps going to our dispute resolution panel if
the company asked to do that.So we
would go through all of those mechanisms as we sort of wind our way there.

Again,
we're hoping that input from the panel if the product is approved, working hard
on designing the studies well, whatever, can avoid those kinds of issues.

CHAIRPERSON
TALAMINI:Any other questions for Dr.
Gardner?

(No
response.)

CHAIRPERSON
TALAMINI:If not, thank you very much.

DR.
GARDNER:Thank you.

OPEN PUBLIC
HEARING

CHAIRPERSON
TALAMINI:We will now proceed with the
first of the two half‑hour open public hearing sessions of this
meeting.The second half‑hour
open public hearing session will follow the panel discussion this afternoon.

At
these times, public attendees are given an opportunity to address the panel, to
present data or views relevant to the panel's activities.

I
would like to remind public observers at this meeting that while this portion
of the meeting is open to public observation, public attendees may not
participate except at the specific request of the chair.

I
would ask when persons address the panel now or later, they come forward to the
microphone and speak clearly as the transcriptionist is dependent on this means
for providing an accurate transcription.

If
you have a hard copy of your talk available, please provide it to the executive
secretary for use by the transcriptionist to help provide an accurate record of
the proceedings.

No
individual has given advance notice of wishing to address the panel this
morning.If there is anyone now wishing
to address the panel, please identify yourself at this time.Do we have anybody in the audience?

(No
response.)

CHAIRPERSON
TALAMINI:It does not appear that we
do.Okay.

OPEN COMMITTEE
DISCUSSION

CHAIRPERSON
TALAMINI:Since there are no public
comments this morning, we will proceed to the open committee discussion.We will start with the FDA's presentation on
nocturnal home hemodialysis.The first
speaker for the FDA is Dr. Carolyn Neuland.

1.REGULATORY BRIEFING

DR.
NEULAND:Good morning.Thank you, Dr. Talamini.

As
Dr. Talamini has said, I am the Branch Chief of the Gastroenterology and Renal
Devices Branch.And this is the branch
within FDA that is responsible for reviewing medical devices for hemodialysis
products, which is the main topic of today's session.

I
would also like to take this opportunity to welcome each of you to the session
today and thank you again for taking time out of your busy schedules to share
with us your clinical experience and your scientific knowledge in the area of
home nocturnal dialysis.

Before
we get into the in‑depth discussion, I would like to cover a few
introductory‑type issues.The
first thing I would like to do is introduce the members of the Gastroenterology
and Renal Devices Branch who are present today.These are individuals who review the medical devices related to
hemodialysis.

I
will then discuss with you very briefly an update on the advisory panel that
occurred in January 2003 and let you know the outcome of that deliberation that
you had at that time.

I
will then go into the regulation of hemodialysis devices very briefly.I know you covered this last night in your
training, but I will just touch upon how we review hemodialysis products in
general.And then I will discuss the
guidance documents for hemodialysis that currently have been written.

Finally,
I will give you a working definition today of nocturnal home hemodialysis that
you can work from and then bring forth the main meeting objectives for today's
meeting.

Okay.I am going to announce the members of the
Gastroenterology and Renal Devices Branch that are present.If they would please identify themselves
when I mention your name?We have
present Linda Carr, who was our consumer safety technician, who prepared all of
our slides today.I guess Linda hasn't
shown up yet.

Dr.
Jeffrey Cooper, who is our panel executive secretary, sitting at the head
table; Linda Dart, who is a biochemist in our group, who reviews dialysis
products; Gema Gonzalez, a biomedical engineer, who is very active in the
review of our dialysis product; Dr. Irada Isayeva, who is a polymer chemist in
our group; Dr. Kristina Lauritsen, who is a biologist; Barbara McCool, our
nurse consultant, very active in dialysis; Joshua Nipper, our biomedical
engineer.And you will be hearing from
Joshua Nipper shortly, who is going to give you an overview of conventional
dialysis equipment.

Rebecca
Stephenson, a chemical engineer in our group.She is the youngest person in our group and the newest to join FDA.Kellie Straughn, our clerk‑typist; and
then Mr. Richard Williams, a mechanical engineer in our group.I'm sure many of you have talked to these
individuals over the history of reviewing these products.Okay.

One
of the requirements for the advisory panel process is to ensure that the
advisory panel members receive adequate follow‑up and feedback on the
outcome and the status of previous products that have been brought before this
advisory panel.Therefore, I will take
the next couple of minutes to update you on the status of the PMA that was
brought before the advisory panel in 2003, the last session of this group.

This
device is what's called the Enteryx procedure kit.It is marketed currently by Boston Scientific Corporation.This device is a solution which is injected
into the lower esophageal sphincter for the treatment of gastroesophageal
reflux disease in patients who currently are responsive to pharmacological
therapy.

This
product, this PMA product, came before the advisory panel in January 17th,
2003.And the recommendation at that
time was for approval with conditions.The conditions were related to modifications to the physician labeling;
modifications to the patient labeling; and for a post‑market study, as
you just heard.That was one of the
primary recommendations.And the study
was to occur for three years post the last injection of the material.

Well,
I am happy to say we did approve the PMA following that recommendation.It was approved on April 22nd, 2003.A post‑approval study was a
requirement of the conditions of approval.It was a three‑year post‑approval study, which required the
enrollment of up to 300 patients, some of which were patients that had already
been in the initial study and were going to be followed out to three
years.Others were new patients that
were going to be enrolled.The 300
patients were required.

We
also were interested in looking at reinjection of the material in that
study.And I am also happy to say that
study is actively ongoing.We receive
annual reports from them.The study is
not completed yet because it was only approved in 2003, but the study is
actively ongoing.

Now,
I just wanted to mention briefly that there have been a few MDR reports that
have come out on this device which have shown adverse events related to the
transmural injection of the Enteryx material from improper implantation
techniques.This is typically physician
related in how they are injecting the material.

This
transmural injection has resulted in the placement of the Enteryx material into
the aorta, the media steinum, or into the plural space in a few patients.In one example, the material may have
through the aorta through a branch of the right renal artery.

In
addition, one patient who had inadvertent transmural injection into the wall of
the aorta developed an aorta or anterial fistula, which that patient then,
unfortunately, succumbed to bleeding and passed away.

As
a result of these types of adverse events, again, I wanted to emphasize this is
physician‑related.It is a
technique that is occurring.It was
determined that we needed to have some additional labeling changes to the
PMA.And the company has worked
extensively with us on this.And we
have rewritten the labeling and instructions for use, stressing the proper
technique for injection of the material.We will continue to monitor this closely.And I think that with the additional training, this problem
should go away.

Okay.Now I would like to turn our attention to
the main topic of today, which is nocturnal home hemodialysis.How does FDA regulate hemodialysis products?Well, most all of the products for
hemodialysis are regulated through a 510(k) process.These products are class II medical devices.The classification process is risk‑based.Class II products generally are considered
of a moderate level of risk.

There
are some requirements for class II devices for general controls and special
controls to ensure the safety and effectiveness of these products.General controls include such things as
registration and listing the submission of a pre‑market notification,
quality system regulations, and things of that nature.And special controls are such items as
guidance documents development following performance standards and other types
of safety issues such as those.

As
I said, these devices, the hemodialysis products, are regulated under a 510(k)
process called a pre‑market notification.And these devices are determined when they are marketed to be
substantially equivalent to a device that is already currently on the
market.We call this a substantial
equivalence clearance process.

I
do want to note that currently there are no devices that are currently labeled
and approved for the use of nocturnal home hemodialysis in the United States.

I
said this was a clearance process.Substantial equivalence is determined.And when a device is placed on a market through this 510(k) clearance
process, it is determined to be as safe and as effective as the predicate
device.

Performance
data is usually required for these submissions.Typically it is bench studies.However, if there are new modalities, we frequently require clinical
studies.And we have required clinical
studies for devices in hemodialysis that are going to be put into the home
setting.

Hemodialysis
products are listed in the Code of Federal Regulations under a number of
classifications.The primary ones for
hemodialysis equipment are under 876.5820 and 876.5860.The difference between these two
classifications has to do with whether an ultrafiltration controller is added
to the system, and the 5860 is for high flux dialyzers.Both of those types of devices are
classified under those classifications.

We
have a number of other classifications that deal with dialysis products.I am bringing this out so that you realize
we don't bulk everything into one classification.We have tried to spread out these different products into
different regulations.

We
have a separate classification for sorbent regenerated dialysis delivery
systems for hemodialysis.We also have
a separate regulation for water purification systems.Again, we have products for peritoneal dialysis that are separate
from hemodialysis.

And
we have blood access devices and accessories for the dialysis process.I just would note that these currently are
class III, but they are still reviewed under the 510(k) process.We are looking into the reclassification of
these products currently.

We
have written a number of guidance documents for hemodialysis products.They have included guidances for
conventional high‑permeability dialyzers, guidance documents for the
hemodialysis delivery systems.We have
a guidance on the reuse of hemodialyzers.And we also have a fairly detailed guidance document on water
purification systems, which is a significant component that raises a lot of
safety issues in the dialysis process.

Now,
it's important for me to bring these issues out to you because today you are
going to be challenged with giving us advice which may lead to the development
of a guidance document for nocturnal home hemodialysis.So I would just like to make a couple of
comments about guidance documents.

Guidance
documents are actually listed in the Code of Federal Regulations.And it stated that the guidance documents
are documents prepared for FDA staff, applicants, and sponsors, as well as the
public that describe the agency's interpretation of or policy on a regulatory
issue.

Now,
guidance documents represent FDA's current thinking on a specific issue or a
device.Guidance documents do not
establish legally enforceable rights or responsibilities.They do not legally bind the FDA or the
public.

An
applicant may choose to use an approach other than the one set forth in a
guidance document.However, the
alternative approach must comply with the relevant statutes and regulations
that have been written.

So
just keep that all in mind as you go through your deliberations today and your
discussions and give your advice because I do hope that we result in a guidance
document for nocturnal home hemodialysis.

Okay.Well, this leads us into the discussion of
today's main topic:nocturnal home
hemodialysis.And I would like to give
you what I consider a working definition for this topic today.You may add or take away and discuss this
further, but this is the definition that we have come up with.

Nocturnal
home hemodialysis is a type of hemodialysis performed in the home by the
patient while the patient is asleep.Typically this may be done at night.It is done over a six to ten‑hour period using slower flow rates
for the blood and dialysate or generally slower flow rates and is frequently
performed five to seven days per week.

Today
we would like you all to engage in a discussion of this topic of nocturnal
dialysis, and I have here the three main objectives I would see as hopefully
coming out of this meeting.

The
first is to discuss and provide recommendations on the clinical and scientific
issues associated with hemodialysis device design, the labeling, and the
training for nocturnal home hemodialysis.

Second,
we would like you to discuss and provide recommendations on the clinical trial
design to study nocturnal home hemodialysis in the home setting.

And,
finally, we would like to obtain scientific feedback, which can be used to help
in device evaluation decisions on these products in the future and may lead to
the future development of a guidance document for nocturnal home hemodialysis.

Again,
I thank you for coming and for providing us this feedback.And any suggestions, recommendations, or
advice you can give would be greatly appreciated.

I
would now like to introduce the next speaker, Mr. Joshua Nipper, who will be
discussing with you the current conventional hemodialysis equipment that is on
the market.

CHAIRPERSON
TALAMINI:Thanks, Dr. Neuland.I would just remind panel members, jot any
questions down because after all of the FDA presentations, we will have the
opportunity to ask the FDA specific questions about their presentations.

MR.
NIPPER:My name is Joshua Nipper.I am a biomedical engineer with the
Gastroenterology and Renal Devices Branch.And I am here today to talk to you about conventional hemodialysis
delivery systems as they have been currently cleared.

Just
a brief overview of my talk.Again, I'm
going to be talking about conventional systems.I'm going to go over some of the models and parameters that
dialysis device is responsible for.I'm
going to cover some of the alarms that a standard system would have.I'm also going to go over some of the
accessory devices that would be used during a hemodialysis treatment, including
water treatment systems, the hemodialysis blood tubing, remote monitoring
systems, and blood access devices.

Just
a very brief disclaimer.I'd like to
point out that any examples I give in this presentation aren't an endorsement
or criticism of any specific type of technology, device, or company.It is merely to give you an idea of what has
been cleared.

I
would also like to reiterate a point that Dr. Neuland made in that no devices
are currently cleared for nocturnal home hemodialysis.

As
Dr. Neuland mentioned, our hemodialysis delivery systems are cleared under two
different classifications:5820 for low‑permeability
systems and 5860 for high‑permeability systems.I would just like to point out the only real difference between
these two classifications for dialysis delivery systems is the fact that the
high‑permeability systems have an ultrafiltration controller to regulate
the amount of fluid that is removed from the patient.

We
also do have a guidance document available for manufacturers that gives them an
idea of what type of information we are looking for in a 510(k)
submission.This covers the traditional
bench testing that we would be expecting.

What
I have here is basically a schematic of a standard or traditional hemodialysis
system.And I'll kind of walk you
through it here.I apologize if this is
rudimentary review for anyone, but the blood typically is pumped from the
patient through a drip chamber by the blood pump, goes through the
hemodialyzer, and returns to the patient.

Some
of the key features that most systems do have is some form of saline pump.This can be a gravity‑fed or it can be
drawn in by the blood pump or maybe a separate pump itself.Many systems have an anticoagulant pump that
administers either a bolus or a rate of anticoagulant through the entire
treatment.

There
is also a series of pressure transducers here, here, and on the venous
side.Different systems measure
pressure differently.Some measure
multiple sites on the arterial side.Some measure pre‑pump, as I demonstrated here.Some measure post‑pump.And some don't measure on the arterial side
at all.However, all systems are
responsible for monitoring the pressures during the treatment.

On
the venous side, I will use the mouse so as not to blind anyone.We do have an air detector that monitors for
air embolism and keeps any air from being administered to the patient.You also have a venous clamp that will clamp
down on the lines in case of any warning states, any severe warning states, to
prevent blood from being returned to the patient in an alarm situation.

The
system I've demonstrated here is known as a three‑stream system because
you have the water, acid concentrate, and bicarbonate concentrate all coming
into the system, being mixed by the system to form the dialysate of the
prescribed conductivity.Systems that
use this type of technology would be required to have a conductivity meter to
ensure that the appropriate composition of dialysate is being created.

The
dialysate is pumped by the blood pump in a counter‑current fashion
through the dialyzer and back out to a waste.I have also demonstrated some patient fluid being removed and would like
to point out there is a blood leak detector on the dialysate outline.This blood leak detector does not detect any
disconnections or any loose connections in the blood tubing.Rather, it connects broken fibers in the
dialyzer itself.Basically it monitors
for hemoglobin or any pinkness in the dialysate line and will alarm if there is
any blood in that line.

Some
systems do not use the three‑stream and will use either a premixed or
some type of sorbent regenerated dialysate.If this is the case, they can get rid of the mixing system that was
there because the dialysate coming in is already expected to be the appropriate
conductivity and concentrations.

These
systems may or may not have a conductivity meter, pretty much depending on
whether they use the premixed or a sorbent regenerated system.

What
we have here is just a blow‑up of the dialyzer itself.You can see the blood in and out and
dialysate in the counter‑current fashion.What I would just like to point out here is that if the pressure
on the blood side and the dialysate side are approximately equal, your main
soluble transfer is by diffusion alone.

However,
if you do have a higher pressure on the blood side, you have fluid removed of
ultrafiltrate removed.And you do have
solute transfer by convection as well.

During
a hemodialysis treatment, the machine is responsible for monitoring the
parameters listed here.You can see
that it monitors the blood and dialysate flow rates.Typically does this by measuring the pump speeds or rotation
permitted of a pump.Again, it measures
pressure in several different areas:arterial, venous, dialysate, and waste.

From
these pressures, the systems calculate the transmembrane pressure, which is
essentially the difference in the blood and dialysate side.

Patient
fluid removed is also monitored using a variety of methods.And temperatures of blood and dialysate can
also be measured.

One
of the main responsibilities for these machines is alarming in any type of
error state.And hemodialysis alarms
usually come in two different varieties.The first is a yellow or caution alarm.These are the types alarms that indicate poor trends, high pressures,
things of that nature, in the machine.

These
alarms usually can be mitigated, and the treatment can be resumed.If they aren't mitigated correctly, they can
progress to a red or warning alarm.These alarms are more serious and may or may not require the termination
of a hemodialysis treatment.

Most systems have alarms for the following
parameters.And this is not an all‑inclusive
list, but you do have temperature; blood leak detector, as I mentioned before;
any flow rate mismatches, you know, the pump is going either too fast or too
slow.

You
have several different pressure measurements:arterial, venous, TNP, and dialysate lines.You also have warnings if you have excessive ultrafiltration and
too much fluid is being removed.Air
embolism, one of the more important warnings, prevents air from being returned
to the patient.

Systems
that do mix or regenerate their own dialysate will have a conductivity or pH
alarm to ensure that dialysate is of the appropriate conductivity and
concentrations.

Some
systems communicate directly with an individualized water treatment
system.These devices may have alarms
that generate poor water quality or when components of the water treatment
system need to be replaced or serviced.

There
are also system‑level alarms.They include many types of hardware or software failures, power
failures, and things of that nature.

I
have included vascular access disconnection with venous pressure with a
question mark.And I've done this
because most modern systems rely on the venous pressure to monitor for any type
of needle pull‑out or vascular disconnection.

The
problem with using this method is that if a patient's natural venous return
pressure is low and you are using small bore needles with long tubing, you can
create enough resistance in the system to prevent these alarms from being
triggered.And we have had documented
cases of needle pull‑outs in the clinic, and the systems have filed to
alarm.

I
would now like to move into some of the accessory devices.Again, these include water treatment
systems, dialysis blood tubing, monitoring systems, and blood access devices.

As
Dr. Neuland mentioned, water treatment systems are classified under
876.5665.And we do have a guidance
document available for these devices as well.This guidance document tells manufacturers of these devices what type of
information we are looking for in a standard water treatment system.

The
primary job of a water treatment system is to convert potable water meeting EPA
standards to purified water that meets AAMI RD:62 standards.The AAMI RD:62 standard is not sterile
water, but it does give the maximum level of concentrations of contaminants and
things like endotoxins and bacterial contaminants.

These
devices can be designed for multiple patients.And these are the types of water treatment systems that you see in the
standard clinics that deliver to multiple patients or they can be single
patient, more designed to interface directly with the dialysis system.

It's
important to note that the single patient systems often have or need some type
of pretreatment to remove their sediments or chloramines, things of that
nature.

This
is just a basic schematic or flow chart of a standard water treatment
system.These devices are highly
customizable.So not every water
treatment will have each one of these components or may have additional
components as needed.It's a little cut
off here because this is the EPA potable water, and you have any amount of
pretreatment, sediment filters, or chloramine reduction.

You
then go to carbon filters, which are generally in two filters in an in series
known as the worker/polisher fashion.You then would go to a reverse osmosis and a deionization.

The
system I have shown here has an altered filter, which would be responsible for
removing any residual endotoxins or lower, smaller contaminants.And then you have your AME water coming
out.The system I have shown also has a
data out, which could be used to interface directly with hemodialysis device.

Hemodialysis
blood tubing serves the simple function of being just the conduit for
blood.It interfaces directly with the
patient and the dialysis system.It has
a larger section of the tubing that is known as the blood pump segment.And it interfaces directly with the blood
pump, the device.The blood pump
segment has to be fit in very snugly within the blood pump in order to get
efficient pumping.

The
important thing to note about the blood tubing is that there are multiple
connection points that the patient or care‑giver would be responsible for
connecting.That includes the access,
arterial and venous, any pressure transducers that have to manually be fit on
the machine.They have to make sure
that the tubing is securely fit into the air detector and into a roller or
peristaltic blood pump.

Blood
tubing can also be either cassette or cartridge‑based, which interfaces
directly with the dialysis system.And
these types of devices greatly reduce the number of connections that the
patients required for making.Generally
they only have to do arterial and venous and maybe some priming manipulations.

I
would also like to point out that kinked tubing is a significant problem, can
cause hemolysis, which can lead to death.Again, we have had documentation of kinked tubing in the clinics causing
patient death.

Remote
monitoring systems are basically software that interfaces with the dialysis
system.It can be built into the
machine or it can be as an accessory or an add‑on.They're used for basic data
transmission.They connect the machine
to the internet by either a modem or some type of broadband connection or a
local area network.

These
devices transmit real‑time alarms and/or completed treatment data.So they can be used to transmit things to a
nurse's station or over the internet to a remote monitoring station.They can also be used to just send final
data, such as amount of blood processed or length of treatment, that type of
thing.

I
would like to point out that current systems are contraindicated as the sole
method of monitoring a patient during hemodialysis.So to date, FDA has required that there be some form of partner
or some other monitoring for these devices.

Finally,
I would like to mention some of the blood access devices that are
available.They generally come in three
different varieties.There's long‑term
cuffed hemodialysis catheters.These
devices are available both in single and double lumen models.

Catheters
contain alternating luer lock connectors that meet ISO standards for connection
to the blood tubing.This is important
because catheters are less prone to any type of disconnection and completely
remove the possibility of needle disconnection.

There
is also arterio‑venous grafts, which are implanted prostheses that are
designed to bypass sections of native vessels.These devices are accessed with a fistula or graft needle.

And,
finally, there are A‑V fistulas.I'd like to point out these are a surgical procedure and, therefore, not
a device regulated by FDA.The fistula
needles are regulated by FDA, are medical devices, and they use the same luer
locks as the dialysis connectors but, again, aren't prone to any type of needle
pull‑out.

This
concludes my talk.I'd now like to
introduce Dr. Michael Mendelson, who will be talking to you about human factors
and dialysis.

DR.
MENDELSON:Thank you, Josh.

3.HUMAN FACTORS

DR.
MENDELSON:Good morning.I'm Mike Mendelson.And I'd like to thank my FDA colleagues for
the opportunity to speak on the impact of human factors on the safe and
effective delivery of nocturnal home hemodialysis.

Here
are the topics I am going to touch on today.First I want to introduce you to human factors.I'm going to talk about the magnitude of use
error as a cause of adverse incidence, including deaths.

I'll
talk briefly about methods used in the field of human factors.And I'm going to talk about based on human
factors the types of problems I anticipate in the delivery in the home.And I'm going to give a brief list of the
recommendations of our Human Factors Branch.

First
a definition.This definition of human
factors was proposed by one of the pioneers in the field, Alphonse
Chapanis.I won't read it to you, but I
will mention that the emphasis in our field is on the behavior of humans, their
limitations.

As I said earlier, we are interested in
use error as a cause of adverse incidence.And here is a general definition of error, as found in a popular human
factors textbook.

You
will notice again the emphasis on humans and their behavior.And you will notice the words
"effectiveness and safety," which are important to us at the FDA.

Do
we know if use error is really a significant problem in medicine?Yes, we do.I could spend my entire talk going over data, but here just a couple of
pieces that might be interesting, Lucian L. Leape, who is a noted authority at
the Harvard School of Public Health, has mentioned in an interview that you
could load patients into one jumbo jet every day and crash it, resulting in all
of their deaths.And at the end, you
would have 120,000 deaths, which is the number of people he estimates who die
from medical error.

And
a more well‑known piece of data is this."To Err is Human" was released by the Institute of Medicine in
November of 1999.And it blamed use
error for between 44,000 and 98,000 deaths in U.S. hospitals each year.

Now,
is it necessary for manufacturers to pay attention to human factors?Yes, it is.The quality system regulation, which took effect in 1997, requires that
user needs be included in the design of medical devices.

And
hemodialysis units would be in class II, which is one of the classes to which
the supplies ‑‑ and you'll notice I'm emphasizing the words
"user" and "patient" and "actual" or
"simulated" conditions.I'll
touch on that a little later.

There
are three phases in the design and development process of a device where human
factors is required to be included:the
input phase, where a manufacturer would take into account complaints about
previous devices or what is written in the literature or information known
about good design; the output phase, where a comparison is made between what is
known about design needs and what the design of the device is before it's
actually constructed; and, probably the most visible area where human factors
is required is ‑‑ and let's call it the validation phase, where an
actual production unit is tested in a realistic setting with prospective users.

Now,
what areas in the medical environment do we look at in human factors?Of course, we look at the device as the
Center for Devices, but in human factors, we look at it as a system.We look at the environment, where things can
be very challenging.We look at the
user, whose abilities may be limited; and, of course, the device.The outcome could result in safe and
effective care or what we're trying to prevent:unsafe or ineffective care due to use error.

Now,
if human factors is successfully applied to the design and development of a
device, we would like to see the following.Now, these are all areas of what's called the use interface, which is
anything a user would interact with in order to deliver care with a device.

Of
course, we expect intuitive operation, what you'd call user‑friendliness,
but also applies to all of these areas:the displays, the controls, the connections.You have an adverse incidence associated with all of these:effective alarms.

I
have clear and effective labeling listed here, but I want to emphasize that by
applying human factors, we hope to minimize the burden on labeling as a way of
ensuring safety and effectiveness.

This
is noteworthy.When I say "safe
and simple installation, repair, maintenance, and disposal," I would like
to point out that users aren't only the people who are operating the device to
deliver care.They're also the people
whom you may not think about as users, anyone who interacts with the device in
any way.People have died because of
interaction with cleaning staff, well‑meaning relatives, and others.

If
there is only one slide that I can present in this talk, it would be this
one.It's sort of our human factors
mantra that some devices can actually invite people to commit errors because of
poor design.And these design
deficiencies cannot thoroughly be prevented by labeling changes.

There
is an easy‑to‑read paperback called The Design of Everyday Things
written by Donald Norman, which is quite often mentioned in the field as a
source of seven principles of a well‑designed interface.I'm going to touch very briefly on the
seven.

Here
is an example of a device that does not provide good visibility.It's a patient‑controlled analgesia
device, a PCA pump, which was adapted to go home with pregnant women in order
to delay labor.It was used for the
delivery of terbutaline.

Now,
all controls are limited to just these two toggles and a small display, which
is about one centimeter by a centimeter and a half.Through that small window, it was necessary to view approximately
50 nested menus.And users quite often
became lost and were unable to navigate their way back and have to start the
process over again.The authors of this
study, Obradovich and Woods, called this an example of dumb automation.

The
second principle, communicate clearly.Patients have been seriously injured and killed when well‑trained
operators of medical devices did not know in one case what type of radiation
and what the dose of radiation was when they were operating a radiotherapy
unit.

Mappings.Probably the simplest way to mention
mappings is to ask you, have you ever burned an empty pot on the cooktop
because you flipped the wrong control?It can have a serious result in other areas, including medicine, but one
noteworthy area where mappings was a problem; that is, the relationship between
controls and displays or controls and what you're controlling, is in the
nuclear power industry.

Don't
be arbitrary.Be consistent.We all expect to turn a valve
counterclockwise when we want to water our lawns.This is actually a principle that is violated occasionally in
medicine.Older style anaesthesia
vaporizers used in the operating room sometimes would require opposite turning
of the concentration controls in order to accomplish the same thing, which is
increased concentration.

Simplifying
tasks.When Dr. Cooper asked us to
please silence our cell phones, I was amazed at the number of steps people had
to take in order to accomplish that task.Both consumer devices and medical devices are filled with unnecessary features
that increase their marketability but interfere with safe and effective use.

Here
is an example of poor constraints.This
is probably the most well‑known human factors disaster in medicine.Well‑meaning family members and
cleaning staff accidentally severely burned and electrocuted some infants when
they plugged the electrode pins for infant apnea monitors into either a
receptacle or an extension cord.

FDA
responded by requiring something called protected pins.These pins on the ends of the cables could
only be plugged into a dedicated connector for use with a monitor.That's an example of a principle called
protective incompatibility.

Last
principle, design for error.If there's
a critical step that needs to be performed, the user should be reminded in
order to make sure that he or she doesn't accidentally perform that step.For example, when you delete a file or a
folder on your computer, you are asked if you really want to do that.

Now,
when we take a medical device into the home, there are reasons why human
factors are particularly critical.Looking first at our users, working at home, they do not have the
support that one would have in a hospital.They don't have biomedical engineers available to sort out
problems.They don't have supplies and
repair parts.

The
users range in education from perhaps elementary school level to
doctorate.Bear in mind that the
typical reading level of a person in the United States, you will hear different
numbers, but I guess a good average is the sixth grade.

For
the very reason that users need to use their medical devices, their ability to
operate them is compromised, particularly in the areas of vision and sense of
touch and memory.

This
is a diverse country.Many languages
other than English are spoken, another reason why dependence on labeling may
not be the wisest approach.And even
because of cultural differences, people do not look at devices the same way.

This
bullet is a little complex.I'll
explain it.There are papers that we
have read that indicate that hemodialysis can be delivered at the same level of
safety as in the clinical environment.But these authors, D'Amico and Bazzi, pointed out that based on their
research, the clinical level of safety found in the home is due to the fact
that the healthiest patients are doing this at home and they can better
withstand the adverse outcomes that sometimes occur.

Looking
at the environment, when patients go into the clinic, they no longer have to
take care of other people or accomplish other things.In the home, they still have to take care of their families.They have to worry about children and
pets.There are many stresses that they
still face in the home.Of course, the
physical environment in the home is not as well controlled as it is in a
hospital.

Things
as simple as the proper placement of device are often not possible because of
crowding or unstable furniture.Voltage
and grounding can be problems because of old wiring.Temperature and humidity are not well‑controlled.The home environment is probably more
dusty.And there is variance in water
quality.Some homes do not have
municipal water.

Now
I'm going to touch on two examples of problems with hemodialysis equipment that
were not found in the home environment.The reason I'm pointing these out is to show that in the clinical
environment, where you have all of this backup, the results, the outcomes of
these problems were minimized.

We
have to keep in mind that problems like this are going to occur in the
home.No device is perfectly
designed.And we have to be extra
vigilant in order to prevent adverse outcomes.

In
the first example, one piece of hemodialysis equipment instructed the user that
in the event that transmembrane pressure automatic control failed, the user
would be alerted with a code that began with the letters "FL," and it
would be possible to manually control it.

Well,
the users actually tried to do this, but for three of the fault codes, it was
not possible to operate the device.The
result was a recall.And the
manufacturer's solution was labeling.And I mentioned earlier how that can be unsatisfactory.

With
a second device, if a device was not plugged into a ground fault circuit
interrupter, which frequently may not be found in the home, and certain other
conditions existed; that is, certain other settings with the hemodialysis unit,
it resulted in overheating.Again, the
manufacturer sent an important advisory letter to the users.

Now,
what I am going to do now is list some of the concerns I have with medical
devices used in the home, particularly hemodialysis units.

Hygiene
is extremely important in the setup of a hemodialysis unit.The unit should be designed to minimize the
exposure to connections where hygiene is critical.Josh Nipper mentioned the choice of using cassettes, rather than
multiple connections.I understand that
some units may require 15 connections.

As
I said before ‑‑ and I will probably say it again ‑‑ we
need to minimize the need for labeling.Also, because both health professionals and lay users can easily forget
their training and develop habits that may not be desirable, manufacturers may
consider the need for retraining.

Thick
manuals are difficult to deal with for common needs.It's more advisable to rely on on‑screen help or laminated
cards attached to the machine.

It's
not certain at this point how the prescribed dialysate will be prepared.The opportunity for error if it's there
should be monitored so a user does not cause injury by using an inappropriate
dialysate.

The
setup and adjustment of the device should be as simple as possible.What I mean here, "ensure safety of
consumables," I'm reflecting back on infusion pumps, which are a rich
source of human factors disasters in medicine.

There
was an infusion pump which had an administration set; that is, a tubing set,
which included an automatic valve that would pinch shut if the tubing were
removed from the infusion pump.

In
one hospital, a woman in labor had an after‑market inexpensive tubing set
attached.And when the tubing was
disconnected from the infusion pump, this after‑market tubing did not
have this safety device.And she was a
victim of what's called runaway infusion.She was overdosed on the medication, and she died.

It's
critical to prime the blood lines; that is, purge them of air.And users in the clinical environment know
how to respond to symptoms of air embolism.Now, when a patient is asleep, we need to minimize the chance of this
occurring and to alert the user of this particular problem.

Interruptions
in the delivery of hemodialysis occur in the clinical environment.And users in the clinical environment know
how to respond.We have to be certain
that the home user will know how to do this also.

I
may have mentioned before the possibility of inadequate room or opportunities
for proper mounting of a device.I know
of cases where dialysis units were mounted on the floor, even though the
manufacturer intended to mount them on a table because the user wanted to
operate them from a bed and was unable to view the display.

I
mentioned that users are typically medically compromised.And in end‑stage renal disease, they
face the comorbidities of, of course, renal failure but quite often heart
failure and diabetes as well.

Touch
screens are critical.Users should not
be probing for different controls.Quite often, they are not using their glasses at night.And they should not have to look up error
codes.They should learn what
particular failure has occurred with their device without the need for separate
labeling.

Progressive
disclosure refers to the principle of allowing users to get just the right
amount of information.If they're
technophobes and they only want the device to operate, then they should not
have to deal with a lot of technology.

If,
however, they want a device that is very transparent; that is, a device that
lets them know exactly what is going on, particularly when the device is not
operating properly, they should be allowed to get more information.

And
a critical problem with hemodialysis, of course, is the risk of
exsanguination.Based on the evidence
available, it seems that a single‑needle system would allow the greatest
protection from that because during the phase when blood is drawn from the
patient, air would be detected in the line and the system would shut off.

Patient
abilities may be lowest at the start of the session.What I mean by that is these patients are toxic at the beginning
of their hemodialysis session.Consequently, we should not expect their abilities to be as high as even
those of an average patient.

I
mentioned in the home, power supply is not as dependable.There are medical devices which have been
tricky and caused problems that were difficult to detect because error codes
were generated or the device went back to defaults that may not be appropriate.

Design
in virtual guardrails.What that refers
to is the principle of protecting the user from entering dangerous
settings.When a patient is asleep, of
course, we want an alarm that is loud enough or produces the kind of auditory
signal appropriate for awakening them.But that doesn't mean that once they are awakened, their abilities are
the same as they are in mid‑morning.Things should be particularly clear for them.

The
human factors engineering process is what occurs when a medical device is
designed from the concept stage taking into account the human factors needs of
the user.

In
order to do it properly, manufacturers need to apply human factors from the
time they first conceive of a new design.The advantages are it's very easy to design in the needs of the user.During their iterative process, it's easy to
make changes.It won't be as necessary
to stick on warnings and increase the thickness of manuals.And research shows that users appreciate
devices designed this way.And they
last longer in the market.

As
I mentioned earlier, the validation phase refers to actually testing a sample
finished device.And I want to touch on
something that I feel is critical:the
difference between a usability study and a clinical trial.

The
purpose of the useability study is to make sure that the risk of dangerous use
error is minimized when a device is used by typical users in a realistic
setting.This contrasts with a clinical
trial, where we are trying to demonstrate that a device is operating safely and
effectively when used exactly as directed because, as we know, in an actual
environment, devices may not be used where or how exactly they're directed to
be used.

And
in my conclusion, I have five points.We should not assume that users are using the devices in the exact
environment that they are intended for.There are compromises in the user and the environment.

We
need to minimize the burden of training and labeling and ensuring safety and
effectiveness.We should not leave the
patient or user home alone without support.They need the same kind of support, perhaps more, than is present in a
clinical environment.

When
I mentioned design needs, I mentioned complaints from users were one area where
information can be found to improve design.I think it is critical to obtain as much feedback as possible from the
users of the device so the next device can be better designed.And our bottom line I'm just going to
reiterate is we want to protect our users from dangerous use error.

Thank
you.And I would like to introduce our
nephrologist, Dr. Claudia Ruiz‑Zacharek.Thank you.

4.FDA PRESENTATION

DR.
RUIZ‑ZACHAREK:Good morning.My name is Claudia Ruiz‑Zacharek.The reason for meeting here today is to ask
for your help on nocturnal home hemodialysis devices regarding optimal device
design for actual use conditions, adequate labeling for minimizing error,
appropriate training for successful treatments, risk analysis to minimize
unforeseen problems, and clinical study design to demonstrate the safety and
effectiveness of the nocturnal dialysis device under actual use conditions.

Currently,
as has been mentioned before, there are no devices that are specifically
labeled to perform nocturnal dialysis.In my talk, I will cover some background information on this issue,
specific issues on nocturnal home hemodialysis.And I will ask for your help for an optimal design of the
clinical studies to address our concerns related to this modality.

The
background information will break it down in demographics, a brief review of
the literature, definitions, and nomenclature.The most common form of renal replacement therapy in the United States
is in the form of hemodialysis.This
typically takes place in a center four hours per treatment three times per
week.This is what we call conventional
dialysis.

One
of the main features of conventional dialysis that I would like to point out is
the presence of medical personnel.A
patient has a passive role during the treatment from measuring the patient's
vital signs to accessing the Aksys or getting the weight to initiating
treatment, troubleshooting through treatment, ending the treatment.All of this is done by medical personnel.

This
is significantly different to our subject today, which is nocturnal home
hemodialysis, where the treatment is actually performed at home by the patient,
typically at night and while he sleeps.This is done in the absence of medical personnel.And that is one of our main concerns
today.And a patient is usually the
performer of the treatment.

The
interest is shifting to different treatment schedules, away from the
conventional hemodialysis described previously.And the most promising change with strongly favorable literature
accumulated over the last few years is daily hemodialysis.

One
of the forms of daily hemodialysis could be short daily.Basically it is all in the same modality of
providing more frequent, more intense hemodialysis than the conventional
dialysis as we know it.

Nocturnal
hemodialysis also is referred as nightly hemodialysis.The subject today specifically is the home,
the nocturnal home, hemodialysis, which could be long nocturnal or sometimes
also called slow nocturnal.

In‑center
nocturnal hemodialysis is not going to be considered today as the presence of
medical personnel is still available.So it's not much of a concern to us.

So
nocturnal home hemodialysis is performed at home by the patient in the absence
of medical personnel.Frequency has
been reported to range from five to seven nights a week.The length of treatment is about six to ten
hours per night depending on the prescription.

Blood
flows tend to be also slower than conventional hemodialysis with blood flows
reported to be 200 to 300 mL per minutes.Dialysate flows range from 100 to 800 mL per minute, also depending on
prescription, but the usual dialysate flows are about 300 mL per minute.

According
to the United States renal data system, the prevalence of patients on
hemodialysis in the United States is about 281,000 patients, out of which 843
have home dialysis, are home dialysis patients.

According
to a publication by Dr. Lockridge in 2002, there are 115 nocturnal hemodialysis
patients distributed in about 13 centers in North America.

The
characteristics across this population in North America, it's about 14 percent
of diabetic nephropathy.And I would
like to compare this with the U.S. demographics of about 45 percent of diabetic
nephropathy in the dialysis population.Let me point out also that diabetes is the leading cause of end‑state
renal disease patients leading to the need for renal replacement.

This
is important for us to consider because diabetic nephropathy or patients with
diabetic nephropathy tend to have more comorbidities than patients with other
etiologies.

So
there is a merging body of evidence that more frequent hemodialysis offers
superior treatment than conventional hemodialysis.And this is just a small sample of the body of literature
available, but the reason I included this slide is to point out that these
studies or these publications are non‑randomized trials.Most of them are prospective.Some of them are retrospective.And the majority have a small number of
patients.Most of them are single arm,
although there are a few of them that have matched controls.

Both
modalities of short daily or nocturnal dialysis have been associated with
significant clinical benefits, including blood pressure controls.Most of them report or, in fact, all of them
report an improvement in blood pressure control to the point where patients
need to decrease a lot of the anti‑hypertensive medications they're
already taking.

Calcium‑phosphorous
control is also improved.Some of the
patients actually need to reduce the phosphate binders that they are
taking.Some reports also suggest that
additional phosphorus is necessary to keep a normal phosphorus level.That is actually a new thing for
hemodialysis patients in which calcium‑phosphorus control is actually
very difficult to control.

Anemia,
on the other hand, has not shown significant improvement on the patients on
these studies.Some of them have
actually reported increased epoetin and iron mean.

Other
benefits associated with this type of more frequent dialysis include the
reduction of number and severity of dialysis symptoms and the fatigue
associated with the hemodialysis.And
the time to recuperate from a dialysis treatment is also reduced.

Improved
serum albumin.This is also a good
thing.End‑stage renal disease
patients tend to have low albumin.And
that is a poor prognostic factor.

There
are also no fluid or dietary restrictions reported in certain patients.This is also in terms of improving the
quality of life for a patient.They
also have improved the sleep patterns.Pierratos in 1999 reported a reduction or correction of sleep apnea.

So
now we will concentrate on nocturnal hemodialysis issues that we would like you
to consider.Let me just remind you
things that we are going to cover are the device design and components, human
factors issues, water quality, use of a partner, and remote monitoring vascular
access and extracorporeal circuit connections, labeling, and lay user training.

Let
me remind you again that our concerns with a conductor in home hemodialysis
compared to conventional hemodialysis is the role of the patient in
conventional dialysis is actually the passive recipient of hemodialysis while
in nocturnal home hemodialysis, the patient has an active role.He is the performer of the treatment.The patient needs to troubleshoot.Basically while he is asleep, he needs to
wake up to the alarms.

To
review what Dr. Mendelson said on human factors, the objective to include this
in the device design would be to improve human performance.And for this, the device may need to be user‑friendly,
reduce the likelihood of user error and patient injury, and to reduce the
burden in training and labeling.So
please keep this in mind when considering device design.

So
we would like for you to consider the following features in the device design,
such as redundancy to have a back‑up system in case a safety feature
fails.

What
would be the right adequacy of the alarms?The loudness and sensitivity and ease of understanding and correction
and the possibility of additional safety alarms that are not present in
conventional hemodialysis.

Another
important aspect in nocturnal hemodialysis is to consider water quality.This is because the exposure to water is a
lot higher in nocturnal hemodialysis.Compared to conventional, hemodialysis patients are exposed to about 360
liters for week in form of dialysate.Nocturnal hemodialysis doubles this amount to 600 to sometimes more than
a liter a week depending on the device and depending on the prescription and
the flow of dialysate.

Just
to let you know on the review of the standard water quality is a total viable
microbial count of less than 200 colony‑forming units per mL and an
endotoxin concentration of less than two endotoxin units per mL.So should higher standards of water quality
be required for nocturnal hemodialysis since the exposure to the dialysate is a
lot more than conventional dialysis?

So
other issues to consider in regards to the modality itself are going on with
water quality concerns, the type of water systems available right now,
treatment systems, is reverse osmosis, deionization, or a combination of both.So which system would be appropriate for a
patient to take home and perform nocturnal hemodialysis?

The
water source on how to manage changes in the quality of municipal ‑‑
in the case of municipal water suppliers, another issue that is concerning to
us is monitoring.Raija in 2003
suggested that nocturnal dialysis could be done without a partner.His study was 59 patients, prospective
study.Out of these 59 patients, 13 of
them were actually in nocturnal dialysis without assistance.

The
conclusion was that there were no increased technical difficulties or increased
alarms or safety issues in regards to this.He based this conclusion in about 115 patient‑month experiences.

In
center hemodialysis, there is constant monitoring by medical person.In home hemodialysis, we understand by that
a patient that is awake.So it's also
not too concerning in regards to home dialysis.

The
London daily nocturnal hemodialysis study in 2003 suggests or the conclusion
was that monitoring is essential for the initial three months of nocturnal
hemodialysis therapy until the hemodialysis team is convinced the patient is
stable and compliant.

Now,
they base this ‑‑ again, as I mentioned earlier, this is a
prospective comparative non‑randomized study of about 23 patients with 22
matched controls.However, only 14 of
them were in nocturnal hemodialysis.The rest were in daily dialysis.

Their
treatments ranged from 13 to 602 treatments based on these 14 patients.There were reported in the time of the study
about 4,000 patient nights, out of which there were about 5,000 alarms,
reported alarms.These resulted in
calls, but most of the alarms were due to either slow response by the patient
to the alarms or non‑response.

Most
of the alarms were due to arterial or venous pressure alarms due to the patient
obstructing the blood tubing.So there
were not emergencies.There was no need
to call the designated contact person or emergency services.

The
average number of alarms per night decreased significantly over time.So each progressive decrease from month 3
through month 18 was statistically significantly lower than the value at one
month.And that's why they concluded at
three months.After three months,
monitoring may not be necessary.

Our
discussion wouldn't be complete without talking about vascular access.Let me just review what is available right
now for the hemodialysis and conventional in‑center or home dialysis.

Long‑term
cuffed catheters, it's actually very convenient in terms of using it
immediately after placement.But there
is a disadvantage in the increase of thrombosis, increase of clotting, increase
of infection.So this is actually not
recommended by the DOCI guidelines.

The
next vascular access available is a synthetic graft.And this is a surgical graft.Usually it's PTFE.And it's
usually available within weeks of placement.It's superior.It has a superior
performance than the catheter but not as good as arterio‑venous
fistulas.And that's actually the
recommendations by DOCI guidance.

A‑V
fistulas need some time to mature, sometimes up to three months and sometimes
recommended to let mature longer depending on the surgeon.But they have a much better rate, a superior
rate of low infections compared to the other, to vascular access.

The
concern with the A‑V fistulas and daily dialysis, though, is that with
increased punctures, would that affect the life of the fistula?Quintaliani in 2000 reported an
observational study of 24 patients in daily dialysis, follow‑up of 3.6
years.They concluded that the life of
the fistula is really not affected by the daily puncture, requiring daily
dialysis.

However,
they used dual technique, rather than the single button hole technique.Also, they were using different sites for
puncture, rather than the same puncture, as the button hole technique does.

Other
things that we would like you to consider when it comes to nocturnal dialysis
devices are vascular access location.Would these have an effect in terms of disconnections, infections, or
thrombosis?

Connection
to the device and the use of locking devices or interlinked devices, the self‑cannulation
technique, the training that gets involved for the patient to self‑cannulate,
full detection locking devices, as I mentioned earlier, with a connection to
the device on fluid detection alarms to detect either blood or dialysate leaks.

Pierratos
in one of his papers and many others have reported the use of anureses alarms
to detect blood leaks or dialysate leaks.In the same way, moisture sensors should be included or discussed and
the technique of using single versus dual needle technique.A lot of literature supports the use of the
button hole technique because of the ease of doing it.

So
these are additional features which we think should be addressed by the device
manufacturer as either part of the device or part of labeling.Now, labeling is the operator manual that
includes the warning, precautions, device specifications, instruction for
maintenance, cleaning, and disinfection.

This
includes the physician's instruction for use, which it should also include relevant
data from clinical studies and instructions for use in the caring of the
device.

This
is basically the same thing as the patient instruction for use with the main
difference and important to remember is that this is written for a person with
no medical training or we should assume that they have no medical training.

So
training is defined as the teaching provided by the manufacturer.So the medical expert can train the lay
user.And the lay user is able to use
the device successfully.

So
the aim for the training should be to be able to conduct safe and effective
nocturnal hemodialysis treatments.The
length of training has been reported to be from two to eight weeks.

Agar
in Australia in 2003 and Leitch in the London daily in nocturnal hemodialysis,
NHD, this also depends on the past experience of the patient and prior exposure
to home dialysis or hemodialysis in center or at home.

Let
me add this now.For the purpose of
testing the adequacy of the training, it would be ideal to have patients who
have no exposure to hemodialysis prior to entering the trial.The main reason for it is to test the
adequacy of the training.

So
what we would like to see at the completion of the training is an appropriate
use of the hemodialysis device, interpretation and use of safety features and
accessory hemodialysis treatment itself, on evidence or a test to confirm the
adequacy of the training.

So,
yet, we would like to minimize the burden on labeling and training.So we have come up with a list of risk
analysis that we would like you to consider and see the completeness of this
list.And maybe there are a few things
that we might be missing.

Let
me tell you that none of this has actually been reported in the literature with
the exception of blood loss.And that
might be one of the reasons why anemia has not shown a significant increase or
a significant change, a clinically significant change in the daily treatments.

Inadvertent
disconnections have not been reported.However, once the treatment goes into the broader marketing population,
would the adverse events reported be still applicable to the wider population
and the marketing population?Would
that be still reflective of the results of the trials and the publications?

So
disconnection could, as we all well know, be life‑threatening and if the
patient is asleep may not even realize that he is bleeding.

The
potential increased rate of vascular access infections again has not been
documented.And the psychological
effects could be positive or negative.That is another thing that we need to assess.

So
now we are going to go into the clinical studies.And I will divide this into the purpose of what we think a
clinical study is needed, patient selection, inclusion, and exclusion criteria,
to ask for your help, to ask for your help in the optimal design to test the
device in actual use conditions.

So
the purpose is to demonstrate the safety and effectiveness of the nocturnal
hemodialysis device under actual use conditions.This is not intended to evaluate the long‑term morbidity
and mortality of nocturnal hemodialysis as a therapeutic modality compared to
conventional hemodialysis.

So
our concerns are the patient selection for trial.Can this be reflective of the patient selection when the device
goes for marketing?Again, for the
trial, in order to test the adequacy of training, we would like patients that
do not have prior training or prior exposure to home dialysis.And this is just to test the training.Once it goes to marketing, of course,
patients with prior experience would probably be preferable.

We
would like to make sure that the patient is able to perform the entire
treatment and that the patient is actually able to attend the alarms.So, again, the adequacy of the alarms
becomes an issue.

In
terms of patient selection, there is different literature.And let me go through these three
citations.Agar in 2003 ‑‑
he's from Australia.He included in his
prospective study 16 patients.The
selection criteria was they must be clinically stable for more than three
months on hemodialysis.They should be
psychologically sound, technically adept, stable and have a supportive home and
a history of compliance.So this is
already excluding a large part of the population.

Alloati
in Italy in 2002 also had a non‑randomized prospective study, including
18 patients.Let me point out here the
important thing is the diabetic nephropathy.It's only one patient of 18 patients.And the U.S. population, as I mentioned earlier, is 45 percent.So, again, this type of selection is not
representative of the marketing population in the U.S.

Covic,
this is a retrospective observational study of 286 patients in the U.K.He basically started his analysis since
1960.Initially the patients in
nocturnal dialysis excluded older and frailer patients, exclusively excluded
patients with diabetes, cardiac failure, and multiple myeloma, although that
plan has changed.And now they are
including about 33 percent of diabetic patients.

So
should the following be incorporated into the selection criteria?And that is availability of a partner or the
possibility of monitoring.Patient
compliance, psychological well‑being, and home environment, which most of
these items are already addressed by Medicare, to have an adequate water
supply, adequate sewage, adequate electricity, adequate space, and social
interaction.

So
once patient selection is discussed in regards to an optimal study design, what
would the clinical endpoints be the best to assess this study design in terms
of effectiveness and safety and adverse events?

In
addition to what is conventional dialysis, should a control group be
necessary?And should it be randomized
or should the patient be their own control?The length of follow‑up is also an issue and the sample size.

Let
me just briefly tell you that on home hemodialysis studies, what we have done
is a small number of patients, less than 30.The time frames are an observational period during in center; then the
use in center of the device in question; then a wash‑out period, where
the patient doesn't have this device.And then they go home with the device, and there is continuation of the
study.

So
these are treatment‑related issues include the dialytic composition,
which may change with more intense and more frequent hemodialysis, the
additives on the possibility of using phosphate, as reported by several of the
clinical studies I've mentioned, administration of anticoagulation and the type
of anticoagulation, what kind of dialyzer to use, and whether monitoring should
be encouraged or required, and what type of monitoring, vascular access and
what type of access would give the safest connection to the device and the
practice of reuse.

In
conclusion, we would like your help for eventually creating a guidance document
in creating an optimal device design for actual use conditions, adequate
labeling to minimize error, appropriate training for successful treatments,
risk analysis to minimize unforeseen problems, and clinical study design to
demonstrate safety and effectiveness of the device itself under actual use conditions.

Thank
you.

CHAIRPERSON
TALAMINI:Thank you very much for very
clear presentations from all of the FDA personnel.

I
would like to now offer the panel the opportunity to question the FDA regarding
these presentations.In the interest of
a smooth day, I would encourage you to not ask questions that we know are going
to be discussed or are already within the scope of the questions that we are
going to be going through as a panel, but try to ask questions that are either
outside of that scope or are clarification questions about that which has been
presented.

So,
with that caveat, are there any questions?Dr. Blagg?

5.QUESTIONS FOR THE PANEL

DR.
BLAGG:I would like to raise an issue
about the definition of nocturnal home hemodialysis because there are patients ‑‑

CHAIRPERSON
TALAMINI:A little bit closer to the
microphone, sir, if you could.Thank
you.

DR.
BLAGG:Okay.I would like to raise a question about the definition of
nocturnal home hemodialysis, which in this case is limited to a treatment
frequency of five to seven days a week.There are patients in this country and elsewhere doing it three times a
week or alternate nights.

And
I think that the difficulty comes.What
we need to do is define nocturnal dialysis as dialysis which is done overnight
to any frequency and define five or more times a week dialysis as nightly
dialysis to clarify the difference.

CHAIRPERSON
TALAMINI:So noted.And I think through the day today, it
appears to me as a non‑nephrologist, that there really are two global
issues that we need to deal with.One
is the fact that this is being done at home, as opposed to in a center.And the second is the issue of frequency and
whether it's better for patients to have more frequent dialysis.

But
with that question, do any of the FDA speakers have a response to the issue of
the definition?

DR.
MITCHELL:Hi.My name is Dr. Dianne Mitchell.And I'm the chief medical officer for this division.

I
think those two definitions are fine.What we need to keep in mind, though, is that we will be asking you to
give us guidance for both types of dialysis you identify.

CHAIRPERSON
TALAMINI:Other questions for the
panel?Dr. Sadler?

DR.
SADLER:I would just like to make the
point that a couple of presenters considered the material provided by the
manufacturer to be the training or a large component thereof.And the training actually is the
responsibility of the medical team in the dialysis facility doing the training.

And
the manufacturers will provide background information, but my experience would
say that the further the manufacturers go with the details of clinical steps to
be taken by the team, the more they see themselves exposed to liability.And so they're fairly reluctant to do that.

And
I don't think we should assign them this responsibility except for
characterizing their product, its operation, and the rational hazards
associated with it.

CHAIRPERSON
TALAMINI:So noted.Dr. Hoy?

DR.
HOY:Dr. Mendelson said he felt that
patients might actually be more toxic pre‑nocturnal dialysis than
patients in the center.In fact, that's
not.Perhaps I misunderstood what you
said, that they're certainly not more toxic.They're well‑dialyzed, much better dialyzed than our own center
patients.And their cognitive function
is markedly improved.

DR.
MENDELSON:Yes.I think they didn't explain it
correctly.At the beginning of each
session at night, they are more toxic than they would be at the end of the
previous session.I wasn't comparing
the clinical setting to the home setting.

I
was simply saying their abilities may be compromised at the beginning of a
treatment session relative to the end of the treatment session.

DR.
HOY:I certainly ‑‑

DR.
MENDELSON:Or relative to their recovery
from the treatment session.

DR.
HOY:In my experience, that is not the
case.These patients don't seem to show
a major cognitive difference between the morning and the evenings because they
are dialyzed 48 hours a week.So I'm
not sure that that is a real concern.

DR.
MENDELSON:Okay.Thank you.

CHAIRPERSON
TALAMINI:Other questions?Dr. Lockridge?

DR.
LOCKRIDGE:Yes.On the issue of the human factor ‑‑
and you cited the part about the hospital error.There wasn't anything discussed about the fact that when you
empower a patient, they become much more adept and much more responsible for
their care.

The
factors of the 98,000 deaths per year in hospitals are based purely on the fact
that personnel in the hospital are making mistakes.And I think we have to be very aware that there is something that
is very positive about empowerment of patients.

DR.
MENDELSON:Yes, there is.Now, we do know that error involving medical
devices probably plays a ‑‑ it's not even half of those reported
deaths.It accounts for a minority of
those deaths because so many of these deaths involve medication errors.

But
in looking at home use devices, we feel that the compromises of the patient in
the environment need to be considered to the point where they play a
significant role, just as the fact that although in the clinical role you'll
have a highly trained, experienced person delivering care, that person may be
overtired or may be distracted because of many different responsibilities or
many devices, which pose conflicting operation methods.

I
realize there are patients who are so adept at use of their home use devices
they sort of fall into a pattern.Actually, some patients fall in love with their home devices, and they
will not part with them, even though there are better designed, safer, perhaps
even more friendly devices on the market.I recognize that.

CHAIRPERSON
TALAMINI:Dr. Aranoff?

DR.
ARANOFF:I would like to come back to
something that Dr. Blagg brought up, and that is the definition of this therapy
because, especially if, as Dr. Neuland pointed out, we want to perhaps come up
with a new document, advisory document, I think we need to think differently
about the way that this therapy is defined because if we define it on the basis
of blood flow, 200 versus 400, that is the wrong pathway because you can
exsanguinate very quickly at 200 milliliters a minute, just as you can at 600
milliliters a minute, or if we define it by starting the machine after sundown
versus at sunrise, that's also the wrong pathway.

This
therapy is fundamentally different than in‑center hemodialysis or
previous home hemodialysis in the way that it is monitored, not how fast the
blood goes or the dialysate flow rate or the time of day or the duration of the
therapy.It has to do with the way the
treatment is monitored at home.

Traditional
home hemodialysis, not too differently than traditional in‑center
hemodialysis, is monitored by more than one individually usually, by somebody
who is awake and alert and can respond to traditional kinds of alarms and so
forth.This form of therapy is defined
differently in that patients will be unconscious when the therapy is performed,
largely.And, therefore, the whole
concept of how we view this therapy needs to be different than simply the
superficial markers of blood flow, dialysate flow rate, duration, or time of
day.

Bob?

DR.
LOCKRIDGE:I agree with you, but I
think that the lower the blood flow rate, limiting the ultrafiltration, and
going slow and long impacts on all the things that you're trying to monitor
that we keep hearing are very bad in center.

When
you run somebody at a blood flow rate of 500, dialysis flow rate at 600, and
you pull 6 kilos in the first 3 hours, they're going to all get sick.The autonomic system is cranked up, and they
get sick.When you do at a 2 to 3
hundred ratio and you only pull 300 cc's an hour, they never get sick.So I think it's clearly a difference.

CHAIRPERSON
TALAMINI:Hold it.Time out.This is all valuable stuff, but I want to make sure that we ask the
questions of the FDA that we want to ask them during this time period.So this is all very valuable, but I want to
make sure we take this time for clarifications or things that are outside the
scope of the questions that we will already be discussing.

Yes?

DR.
MITCHELL:This is Dr. Dianne Mitchell
again.I was just wondering if I could
make a comment in response to Dr. Sadler's comment about device training versus
clinic training.

We
at the FDA do recognize that there is a difference between those two.I think there was a reference to it in one
of Dr. Zacharek's slides.

The
purpose of the discussion today regarding training is indeed for you to address
what you think is appropriate for the device manufacturers to do in conjunction
with training on their device.

Thank
you.

CHAIRPERSON
TALAMINI:Thank you.

Other
questions for the FDA?Dr. Weinger?

DR.
WEINGER:Yes.I think many of the issues with regard to the use of these by
patients is going to depend somewhat on what percentage of this 280,000
patients ultimately would be subject to this.

So
are there any estimates from the FDA of what kind of patient population?Right now there are 100 or 150 or
something.When these devices become
available, how many are going to be on this?

DR.
RUIZ‑ZACHAREK:Yes.It's hard to predict.Right now I wanted to mention that there is
a very limited number of patients.And
these are highly selective in each trial.When it goes to the marketing, that selection may or may not still be
there.

What
I wanted to point out is the patients in the general population on dialysis in
the United States have a lot more comorbidity than the patients included in
these studies. With the impact of a device going into the market, specifically
labeled for nocturnal home hemodialysis, we don't know.

But
we want to make sure we take the safety precautions to deliver safe and
effective treatment among that population.

CHAIRPERSON
TALAMINI:Thank you.

Who
has not?I think let's go back to Dr.
Hoy.

DR.
HOY:Just a comment, Dr. Ruiz.I think there has been an evolution of the
selection of these patients, which isn't perhaps apparent in some of the
published literature since it's usually two to three years behind what actually
has occurred.

In
our center, we have trained 49 patients.Seventeen of them are diabetics.They have all of the diabetic complications, including peripheral
neuropathy and difficulty with manual dexterity, blindness.We have one legally blind patient hose
husband is deaf.The two of them can
run this machine at home.We have a
matched set there.

The
patients, 41 out of 49 of our patients were over 200 pounds.These are the hardest patients to dialyze
adequately.They were all excluded from
the hemo study.These are patients that
we're using nocturnal dialysis as salvage therapy for.They're the ones who have the unquenchable
thirst, you know, who gain six to eight kilos between treatments and
cardiomyopathies with ejection fractions in 5 of our patients with less than 25
percent.

So
I think that you have to be careful concluding that we are self‑selecting
these patients.There is only one
absolute criterion that our patients have to have.And that is they have to want to learn this.And we have not yet found a single patient
we could not train if they wanted to learn it.

And
our most difficult patient was a child psychiatrist.She took 79 days to learn how to do this.

DR.
RUIZ‑ZACHAREK:Yes.As you said, the trends have changed.In fact, most of the benefits or the people,
some of the patients that most benefit from this type of modality are
overweight patients, patients with sleep apnea.Pierratos have included patients with overweight that demand a
lot more dialysis than the conventional hemodialysis can provide.

That's
why sometimes diatolic flows go up to 800.Sometimes the blood flows can go higher than what nocturnal dialysis
tends to have, slower than conventional.

So
yes, the benefits, you know nobody can deny that the benefits will, the
suggested benefits by the published literature, the patients that most will
benefit from that are the patients that may have already been excluded by other
clinical trials or by other publications.But we cannot deny that they're probably going to be the ones that most
benefit from it.

CHAIRPERSON
TALAMINI:I would warn the panel our
time for asking questions is running very quickly.So succinct if you can, please?Dr. Lockridge?We'll just go
around one more time, and then we'll ‑‑

DR.
LOCKRIDGE:This is to Dr. Neuland.It really comes out that the guidance
document is one of the things that appears to be that we are going to try to
develop here today.Is there any
direction that you would give to us as panelists of how to help you do
that?I mean, I think that's a critical
issue that we are trying to develop.Tell us what are our directions or try to educate us a little bit more
about that.

DR.
NEULAND:Well, I think that the two
main issues have already been brought out, and that is whether you have any
recommendations on design of a device that would make it safer for the medical
community.

Because
in the guidance document, our overall plan is to put in issues that need to be
addressed in a submission to the FDA for marketing clearance.And that would include anything to do with
specific issues related to the design of the device or with the clinical trials
that we hope to have done to support these marketing clearances.

DR.
AFIFI:Dr. Talamini?

DR.
NEULAND:Plus, you're going to be
addressing these, I think, ‑‑

CHAIRPERSON
TALAMINI:I'm going to go around real
quick.

DR.
NEULAND:‑‑ in the
questions that you're going to cover today.

CHAIRPERSON
TALAMINI:Dr. Blagg?

DR.
BLAGG:I don't know whether we're going
to cover more about the question of patient selection later on.Are we or not because I would like ‑‑

CHAIRPERSON
TALAMINI:Yes.

DR.
BLAGG:Okay.

CHAIRPERSON
TALAMINI:It is certainly within the
questions.

DR.
BLAGG:I will save the comment for
later.

CHAIRPERSON
TALAMINI:Yes, Dr. Gibson?

DR.
GIBSON:Just a clarification.Josh Nipper said that FDA labels current
systems as contraindicated as the sole method of monitoring patients during
hemodialysis.Is that aimed at
nocturnal hemodialysis?Is the FDA now
regulating that in some way or is this ‑‑

MR.
NIPPER:Well, that was in relation to
any remote monitoring systems.That was
part of our initial concern that the current information we had was limited to
in‑center type devices.So we
were concerned when we see devices that connect to the internet and can
transmit data remotely.That was one of
our concerns for nocturnal or just general home use.

So
both of those were contraindicated or all of the devices have been
contraindicated as the sole method.So
as long as there is a partner there, we kind of are hands off on whether a
device goes home under practice of medicine, but it is contraindicated without
a partner.

DR.
GIBSON:So you label it for that.And if someone sends a patient home now
without a partner, you would if you found out about it take some steps?

MR.
NIPPER:Well, I mean, that would be
right there under practice of medicine.A physician can send any device home that they want to.It does provide guidance to the physician
that we do not think that the remote monitoring should be the only way to
monitor the patient.

CHAIRPERSON
TALAMINI:Perhaps I could ask somebody
from the FDA at this juncture to clarify for us the practice of medicine issue
versus FDA guidelines because that is going to play so vitally into the
discussions today.

MS.
BROGDON:The guidance that we will
eventually be developing is guidance for the manufacturers, what they should
submit to us in order to get the labeling and the clearances that they desire.Regardless what gets cleared, it's the
physician's right to use a device as he sees fit in his professional
judgment.So we regulate the
manufacturers on what information and what devices they can supply.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Afifi?

DR.
AFIFI:I have a fundamental question
about policy that relates to a 510(k) pre‑market notification.The question is probably for Dr. Neuland.

When
we are required to see whether something is demonstrated to be substantially
equivalent to an existing device, the process is similar to an evaluation
process.And the question, then, are we
evaluating just the process; in other words, the delivery of whatever the
product is supposed to deliver, or also the outcome?

And
that, then, relates to a slid that Dr. Ruiz‑Zacharek presented, where she
said that we need to demonstrate the safety and effectiveness of NHD but not
evaluate the long‑term morbidity and mortality of NHD as compared to
conventional procedures.

DR.
NEULAND:Okay.Hemodialysis equipment currently and all of
the other medical device components are regulated under the 510(k) process.

When
those products are cleared, ‑‑ they're not actually approved;
they're cleared ‑‑ we are determining whether the product is as
safe and as effective as the other devices that are currently on the
market.It's more of a comparison.

What
Dr. Zacharek was trying to say in that slide ‑‑ and she can add to
it if she would like.Basically we did
not feel that this equipment, that it was FDA's role to determine whether
nocturnal dialysis as a modality in general was better than or worse than
current conventional practice of medicine with the equipment that is currently
used.We were looking at whether the
equipment as designed can do a safe and effective treatment basically or series
of treatments for the patient.

So
that's why the studies for morbidity and mortality to us are more of a broad
scope study, one the NIH might sponsor or something like that nature, not an
individual manufacturer would have to demonstrate and prove before their
product could go to market.

DR.
AFIFI:I see.I see.And with that, Dr.
Talamini, I have another point, but I think it can wait for the later
discussion.And that is the role of
redundancy in the design.That is
something that can wait.Is that
correct?

CHAIRPERSON
TALAMINI:Yes.We will certainly be covering that later.

Dr.
Sadler?

DR.
SADLER:I think I am remiss in not
commending all of the speakers for being lucid and clear and making good
presentations.But I do have a few
points to bring up that I think are important.

I
think this is still intermittent hemodialysis therapy.It's a different application.And it's a different site in some ways.But it is not a completely different
therapy.It is possibly improved, but
it is still the same thing.

The
point in that is that if someone should come forward and ask to have their
device labeled for nocturnal hemodialysis, you can be sure that almost
everybody who has one that's already approved for other hemodialysis
applications will be in the same queue very shortly.So we're still talking about hemodialysis and what goes on.

When
Dr. Mendelson talked about alarms, he talked about the sound and what goes on
with them, but we have to realize that probably the worst thing about alarms is
false alarms.It frightens
patients.It frustrates patients.And it causes them not to respond
appropriately to alarms.

As
a former chair of the AAMI committee, I would be remiss if I didn't point out
that in our comments about water, you must recognize that the increasing water
quality requirements have nothing to do with problem‑solving.

There
is no one who has ever been harmed by water that met the original standard enunciated
in 1982.The standard has risen as our
capability to purify water and to monitor what we have accomplished has
increased.

So
that there really hasn't been any rational force for problem‑solving.It's just a matter of admiring our capacity
and responding to that.

And
the final point, I want to remind you that passive restraint levels of safety
are still not absolute.If you have an
air bag, you still have to learn to wear your seat belt.You have to learn to drive.We have to build safer highways and avoid
distractions.There is no single
passive restraint that is going to create safety in an automobile or when you
are attached to a hemodialysis machine.

And
one last point, it's always been my experience since Dr. Blagg and I both did
overnight hemodialysis with our patients almost 40 years ago that the patients
dialyzing at home asleep had the same kind of sensitivity that the mother of a
young child.When the alarm goes off,
they rouse, much better than someone who doesn't recognize that it is important
to them.

CHAIRPERSON
TALAMINI:Comment?You can respond as if it were a question.

DR.
MENDELSON:The time I had for my
presentation was quite limited.And one
of the points I wanted to make about alarms ‑‑ well, several ‑‑
was it's my understanding that the false alarms outnumber the legitimate
alarms.

And
what I am concerned about in the home at night is the effect on the patients
psychologically and physiologically if he or she is roused over and over and
over again.

We
know that interrupted sleep has an adverse effect on the patient's health.And whether this problem is limited to the
patient's health or the patient's health and their ability to operate the
therapy, I'm wondering if people knowledgeable about the physiology of sleep
can address that.

Thank
you.

CHAIRPERSON
TALAMINI:Thank you.So I think we will close the questions to
the FDA and again thank the FDA presenters for very clear presentations.

What
I would like to do is call for a ten‑minute break, but let me just frame
the rest of the day quickly before we do that.We have a Herculean task to cover these eight questions.We could probably spend one day on each
question.So it's going to be
absolutely vital that we move along quickly.And hopefully everybody will not hate me by the end of the day in
driving the committee towards doing so.

But
I would like to take a quick ten‑minute break.My objective is going to be to do two questions and then break
for lunch.I would remind the committee
not to discuss the issues that are at play here outside of the room, as all of
the proceedings here do need to be public and on the microphones.

So
we will reconvene in exactly ten minutes, at 11:34.Thank you.

(Whereupon,
the foregoing matter went off the record at 11:24 a.m. and went back on the
record at 11:34 a.m.)

CHAIRPERSON
TALAMINI:I would like to call the
panel back to order.Dr. Ruiz asked for
the opportunity to respond to some of the comments and questions.So, Dr. Ruiz, if you could do so now?Sixty seconds, if possible, please.You could use this one over here perhaps.

DR.
RUIZ‑ZACHAREK:I would like to
make some comments on the concerns you raised about nocturnal dialysis and
hemodialysis being basically the same modality.It could be.It's
basically hemodialysis.

And,
as Dr. Pierratos said in one of these publications, any type of conventional
hemodialysis machines could be used for nocturnal hemodialysis.

The
concern comes when we send these devices home with a patient that may or may
not have the experience or the appropriate training.So that's our concern.It's not the fact that they have hemodialysis itself because this is the
same modality, but, as somebody else pointed out earlier, it is the
monitoring.That's significantly
different from conventional dialysis and home nocturnal dialysis.

The
other thing that I would like to point out is on the quality of the water.Before all of these standards, actually,
patients were being dialyzed with a little bit higher content of aluminum.And they were having a lot of problems.

So
the question is now we haven't had any problems with the new standards, but
would this be still applicable for patients that are exposed to a much higher
volume of water in terms of dialysis or do we need to regulate that or do we
need to change the quality in the water in former dialysis for patients that
are undergoing nocturnal dialysis?

And
those are the issues that we would like to raise and have you discuss on them.

CHAIRPERSON
TALAMINI:Thank you.

DR.
RUIZ‑ZACHAREK:Thank you.

CHAIRPERSON
TALAMINI:So all of those are points
that we will be getting to.So this
meeting now continues with the panel discussion portion of the meeting.Although this portion of the meeting is open
to public observation, public attendees may not participate except at the
specific request of the panel.

Now,
again, some comments on our task today.We have eight questions, which all of the panel members had the
opportunity to study prior to the panel meeting today.And if you take the time remaining, the
number of panel members, and the questions, that leaves about a minute and a
half to two minutes per panel member per question.

And,
again, we could probably spend a day on each of these questions.So I'm going to have to be very tough with
folks, unfortunately.

I
would like to begin, however, by offering the opportunity for each panel member
to offer any general comments.I would
ask you please to limit them to about 60 seconds, really the most important
points.

And
I think since we have already had a fair bit away from the right side of the
table, I'm going to start over on the left side.If you don't have any general comments, feel very free to pass.We would love you for it, but we would also
love to hear your comments.

Ms.
Moore?

MS.
MOORE:Yes.My only comment is that in reading the material, my major concern
was that we have this technology, which is customarily used in a hospital
setting or a clinic of some sort, with professionals in charge.And I was still concerned.

And
I was very much interested in the doctors over there who mentioned the fact,
you know, that they had had experience with patients who were on nocturnal
programs, but I know that we are going to have patients with varying amounts of
abilities, ages, all kinds of conditions that may mitigate against some of
these people using the technology to the best that the technology could offer.

And
so I guess my major concern was some kind of safeguards so that these people
who may not be as educationally able or the elderly persons or people of that
sort would be able to use this treatment to the best of his or her ability.

And
one other thing, the contact, you know, what happens if things go wrong.I was looking to see if there was any
consideration given to making contact with someone without being automated.In other words, if there is an emergency,
who do you contact and will not get an automated message but you would get a
person?

CHAIRPERSON
TALAMINI:Thank you.You mean not get caught in a voice mail
trap.

Dr.
Duffell, your general comments?

DR.
DUFFELL:Yes.I think one thing that is going to be important when considering
the questions today, which has already come up briefly in Dr. Neuland's
remarks, is about the design of these products.

CHAIRPERSON
TALAMINI:A little closer, please.

DR.
DUFFELL:And we need to be mindful in
our deliberations that we probably shouldn't be trying to actually design
products here at this panel but, instead, raising the issues which the
manufacturers need to address in their designs because they may have creative
ways that we haven't considered.

And
then my second point is also to keep in mind that it also seems like from one
of the prior FDA speakers is that the issue that we are really looking at here,
in addition to safety and effectiveness of the products, is also the useability
of the products.

I
think that one of the speakers brought to mind the difference between a
clinical trial and a useability study.So I think what we are really looking at here is making sure that these
things are useable more than they are effective.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Schulman, general comments?Sixty
seconds, please, if possible, or we can come back to you.

DR.
SCHULMAN:If you can come back, that
would be good.

CHAIRPERSON
TALAMINI:Sure.

Dr.
Sadler?

DR.
SADLER:I think I made mine, but in
response to Dr. Ruiz, I do believe that if you look at the water standards, the
1982 standard was fairly complex and comprehensive.And what we have done is to incrementally approve it.

But,
as I say, there hasn't been a problem to force those increments.We have only improved it as our ability to
do so occurred.And I guess in
admiration of our accomplishments, we raised the standard.

You
said in your comments that you worry about the training.And I'm afraid that FDA has to relax about
that because you can't regulate it.And
we just have to get that done.And that
becomes our responsibility in our field.

CHAIRPERSON
TALAMINI:Thank you, Dr. Sadler.

Dr.
Afifi?

DR.
AFIFI:I have no general comments at
the moment.I will have several
relating to design especially later on.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Aranoff?

DR.
ARANOFF:One additional thing that we
haven't mentioned is that although there are no predicate devices for nocturnal
home hemodialysis, there is a great deal known about nocturnal peritoneal
dialysis.

And
some of the concepts, although the consequences of failure of the treatment or
danger of the treatments are very different with peritoneal dialysis and less
so, but some of the concepts about design of monitoring and so forth might be
applied from that, might be drawn from that.

CHAIRPERSON
TALAMINI:Great.Thank you.

Dr.
Kalota?

DR.
KALOTA:I think we need to keep in mind
that this technology is never going to be for everyone.And we can't try and make it for everyone.There are still physicians who are going to
make the decision whether a patient they feel is competent or not and then in
the training, are they still competent to do it and that we need to make it
safe for those who both patient and physician feel are appropriate to do so.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Gibson?

DR.
GIBSON:Just very briefly.In most of the material that we have when
psychological is mentioned, it's mentioned in terms of risk and monitoring for
detrimental effects.

I
would like to congratulate Dr. Ruiz‑Zacharek for mentioning the possible
benefits of home dialysis, which may be considerable and which I don't think we
should lose sight of during the deliberations today.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Weinger is our panel expert on human factors.So I would void my 60 seconds and offer you a few minutes if you need
them for your introductory comments.

DR.
WEINGER:I'll just make two short
comments.First, the data that I have
reviewed on this shows tremendous promise.And I think that this methodology and the devices associated with it are
going to be a superior method for a subset of patients.

But
the data that to date is based on experience of individuals who have many years
who have evolved a practice ‑‑ and the reality in the future with
these devices is they are going to be aggressively potentially marketed to
clinicians who don't have those years of experience.And they are going to be trying it for the first time.

Our
obligation as advisers to the FDA is to promote patient safety.And I think that we need to develop
guidance, strong guidance, to industry about the design indications and
training that maximize safety under those circumstances.

I
have to disagree with Dr. Sadler about training.In fact, training is well within the FDA's purview.And, in fact, carotid stents is a good
example, which there are now regulations that say every user, in this case
clinicians, rather than patients, every user, must undergo rigorous simulation‑based
training before they can use the device.And it's within the FDA's purview to make similar requirements for patients,
not that I am necessarily advocating that at this time.

The
last point I wanted to make in response I think to Dr. Lockridge was that
clinicians make user errors.In fact,
there's a study by Baden in 2001 involving all of France where they showed the
use errors were the most frequent cause of all medical device incidents and the
second most common cause of deaths associated with medical devices.

Now,
these are experienced, highly trained, highly educated individuals using a full
range of medical devices.Now we're
talking about patients, who are going to be far less educated and perhaps less
well‑trained, but the issue is how trained should they be, going to be
using the complex device.

So
use error is clearly a problem.And we
have to help industry and the clinicians deal with it.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Gillespie?

DR.
GILLESPIE:I would just like to say I
hope people will keep in mind as we go through this the potential pediatric
applications of these machines.And I
hope that the pediatric uses will be considered part of the kind of overall
design of the machine, part of the initial labeling, and not an afterthought or
an off‑label use because there are a number of good reasons why children
would be excellent candidates, in some cases even better than adult candidates
for this.And certainly there is a
question all the way back to the first home nocturnal dialysis patient.

CHAIRPERSON
TALAMINI:Thank you, Dr. Gillespie.

Dr.
Blagg?

DR.
BLAGG:I would just like to remind you
as we talk about these machines, that the first home dialysis machine developed
in 1964 was the first single patient machine.It was the first machine which was monitored.And it's really the basis of all of the machines we use now.So a home dialysis machine is where it all
started.

And
the second comment, just a brief one in terms of patients, we did a study once
when we had a psychologist come in and do IQs on 100 successfully, consecutive
successfully, home‑trained home patients.And the IQ ranged from 87 to 147, with an average of 103, which
he told us is just where it ought to be as we did not take the really low‑level
effectives.

Like
some of the previous speakers over here, I think almost anybody technically can
do this if they are motivated and everything else falls into place.

CHAIRPERSON
TALAMINI:Thank you, Dr. Blagg.

Dr.
Moran?

DR.
MORAN:I would like to echo Dr.
Kalota's comments.There are two places
where you can make a choice about sending the patient home.First of all, the health care team can look
at the patient and say, "Does this patient look suitable for home
therapy?"

And
then you have the training period, which is two or four or six weeks.And, again, the patient can be assessed
every day during that training period.And we can abort the home decision at any time during that training
period, and we do.

I
think that the other point that I would like to make is we keep on talking
about professionals doing it in the center and nonprofessionals doing it at
home, but at home you've got one person operating, one device on one
patient.And that is very, very
powerful.The same person is sticking
the same access.

It's
very different from a patient coming into a center, who could have any one of
20 professionals who may or may not have seen this access before.

CHAIRPERSON
TALAMINI:Thank you, Dr. Moran.

Dr.
Lockridge?

DR.
LOCKRIDGE:Well, I think to me the most
overall comment would be that the FDA has invited the clinicians who are doing
this and that this whole process is a process of physician‑patient
decision‑making to see whether or not it's better or worse for the
patient.And we are looking for the FDA
to give guidance to manufacturers to try to certainly make things safe, but
it's that balance.

I
need to have the choice with the years of experience that I have to choose with
patients the FDA needs to protect the overall public.So we need to work together to come up with conclusions.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Hoy?

DR.
HOY:Just I'm more confused than ever
as to whether the jurisdiction is simply the concerns with the machines or
access or ROs or water or dialysate or what or monitoring.I mean, it sounds like the FDA ‑‑
in fact, you could go in any direction you wanted, but it's to go to the
manufacturers ultimately I guess, right?

CHAIRPERSON
TALAMINI:Well, I think that that is
actually a good way to conclude this part because what we really do need to
figure out is what the objective of the day is and how we are going to get
there.

So
we have this set of eight questions, and we need to go through them.You have all looked at them.And they do cover a broad array of topics
and issues, some of which are directly on point of the machines and how they
work and some of them have to do with access and other issues related.So our job for the rest of today is to do
our best to answer those questions and to provide the information.

Now,
again, that is a Herculean task.Let me
tell you how I hope that we can do it.And
we will try this with the first question.What I hope to do is go around the table, give everybody a minute and a
half to address some piece of the question, hopefully a piece that has not
already been addressed earlier going around the table.

If
you've got nothing to say, a pass is just fine.By doing that, hopefully we will get all the way around and have
most of the information and still have time to go back and see if there are
things that we have missed or other things that we need to discuss.

I
would also make it clear to the panel and to the audience that we are not
voting for approval or disapproval of any specific device today.There may be times where I as the chair ask
for a straw vote from the panel to gauge opinion of the panel as a whole, but I
don't want in any way for that to be construed as any sort of official panel
vote of approval or disapproval.If we
do that, it would only be to try and get the temperature of this group here
today.Now, if that strategy does not
work as we move along through the day, we'll modify it as best we can.

So
the way we will actually go through this is to read these questions one by one
and then go around the panel.And we'll
start at a different spot with each question and go clockwise so that everybody
has an opportunity as much as possible to respond.

So
with that, if we could put up the first panel discussion point, which is on
device design?And I will read this
question, "Standard hemodialysis delivery devices contain monitors and
alarms to assess blood pressure, pulse, venous and arterial pressures, blood
and air leaks, temperature, dialysate and blood flow, ultrafiltration rate,
acid and bicarb pumps, end of treatment, and other parameters particular to the
specific device.

"Please
consider and discuss the need for the following additional safety features in
nocturnal home hemodialysis, NHD, treatments and provide suggestions for
additional features.You should take
into consideration the importance of human factors when discussing these
features."

Next
slide."Blood Access, a)
additional safeguards to prevent blood access disconnections; b) alarms to
detect fluid, blood or dialysate, leaks, and a moisture detector at the site of
hemodialysis access."

Next
slide."Central monitoring, c)
software incorporated into the NHD device allowing connection to the internet
for remote monitoring; d) central monitoring of treatment and patient
parameters, such as blood pressure, pulse, venous and arterial pressures."

Next
slide."User‑friendly
design, e) instructions displayed on the machine itself that are clear and easy
to follow for treatment setup, discontinuation, troubleshooting, and
disinfection of the device; f) sensitive and loud alarms with clear
explanations of what they mean and how to respond; g) a justification for
leaving out any standard alarms or features found in traditional hemodialysis
equipment."

So
that's quite a mouthful.It's probably
the biggest question, but our goal is to try and answer that question over the
next 30 minutes or so.

So,
Dr. Hoy, if you could pick a spot in there?

DR.
HOY:Do them all or just a through ‑‑

CHAIRPERSON
TALAMINI:Well, I think it would be
impossible to go a through and still be on time.So perhaps if you could think about what piece of that you would
like to address?

And
if it has already been addressed, please try and pick another piece.And that way, hopefully we will get all the
way around and get back to the place where we can summarize and rediscuss some
of the points.

DR. HOY:So I guess I get to select one out of those.I would like to comment on remote monitoring since we do remote
monitoring over the internet in real time and collect the data from the
dialysis and the alarms.

We
allow the patients to respond to the visual and audio alarms.And our observer who is watching the screen
for 33 patients at the current time responds after two minutes if the patient
doesn't fix the alarm.

I
believe that remote monitoring is useful.I don't think it is absolutely necessary.And I know that there are definitely circumstances where it is
not going to be feasible in patients who are too poor to have a second phone
line and an internet connection.

For
us, we find it very helpful.It's a
very useful way to download information about patients and what is going on
with their treatments and maintain a clear sense of where they are having
problems.It also helps us with some
preventive maintenance on the machines.

It
also allows us to have some sense of who is running and not running each night
because patients when they are well‑dialyzed may tend to take time off.

I
don't believe that you need a partner at home if you have remote monitoring
with an observer.The New York State
Department of Health, which is, believe it or not, harder on us than the FDA or
CMS, feels that we meet the criteria for a partner at home using this as a
virtual partner.

CHAIRPERSON
TALAMINI:Dr. Hoy, just to address Ms.
Moore's question, do your patients have a human they can get in touch with at
night?

DR.
HOY:There is a human being at the
other end of that alarm system from 9:00 p.m. to 7:00 a.m. every night.And if they do not respond to that alarm
within two minutes, he or she will call them up on their second phone and talk
to them.

Remote
monitoring does not prevent bad outcomes of catastrophic events.And we have had one patient have a cardiac
arrest on dialysis.Within 15 minutes,
the emergency squad was there, called both by the patient's wife and by the
observer.The patient was taken to the
emergency room and died.

We
have had one patient have a ruptured kidney while on dialysis.And he was at home alone.And the patient was saved by the observer,
who had the emergency squad called and had the door broken down so that they
could get in.

And
we have had one patient who had ‑‑ that's another issue.Never mind.That's it.

CHAIRPERSON
TALAMINI:Okay.Thank you very much.

Dr.
Lockridge?

DR.
LOCKRIDGE:I would address the blood
access.First of all, I think it's the
physician and the patient should decide the blood access associated with the
types of dialysis.It's not the
manufacturer or FDA I don't think.

I
think there are really three different types of blood access that need to be
addressed:number one, a catheter.Certainly about 27 out of 33 people or 25
out of 33 people I have at home now have a catheter.The infection rate is much less because of an interlink device
and a disconnect device and how the patient is handled.

So
I think standard insulin or catheter use is different in center versus at
home.I think it's a safer
modality.I'm not saying that that
should be the primary access, but I think that FDA needs to have the companies
look at some way of assuring a disconnect.A simple clam shell, a simple interlink device would be of significant
benefit.

As
far as the A‑V fistula and the discharge of the needle or the graft, I
think that the A‑V fistula using a button hole technique and just simple
tapering does prevent the needle from coming out.

We
have done 41,000 treatments at home.We
had never a needle come out in 41,000 treatments with a simple taping
procedure, the arm wrapped with a fishnet, and then the lines anchored to the
upper arm.

So
there are real techniques that make needles in the arm, whether it be in a
fistula in the lower arm in the upper arm, safe.The same thing that goes with a graft.

So
I think, in summary, vascular access should be chosen by the physicians with
the patient.I think all three are
safe.The real focus is on whether or
not, how we assure the connection.And
there are techniques out there with clam shells that can prevent that.

Thank
you.

CHAIRPERSON
TALAMINI:So, Dr. Lockridge, then just
looking at point A, do I hear you saying that additional safeguards are not
needed to ‑‑

DR.
LOCKRIDGE:No.I think that clearly in the home setting,
Fresenius has developed a disconnect system that clamps on the tube.We have a clam shell.There is a disconnect device or a tape.

But
if you use that and the patient applies it ‑‑ and I think human
error does happen.In one case, I had a
gentleman not go to sleep but put himself on and did not put his clam shell
on.He was watching TV.And his catheter became disconnected.And he had to stop the treatment.

So
that's out of 41,000 treatments.But
it's a patient error.So if the
manufacturer can create a way, a red thing that has to be taped around the
catheter or there's a connection device that is built into the tubing that
connects to the catheter or the needle, the needles once they are taped are
okay.So I think we just have to
emphasize that the patient should be responsible in that way.

CHAIRPERSON
TALAMINI:How about alarms, which is
the second point of the access?

DR.
LOCKRIDGE:In the 41,000 treatments,
when the patient puts or sets up or builds the unit, they screw the blood line
into the top of the kidney and in the bottom of the kidney.And then there are valves that connect to
the kidney, the dialysate.

We
have had one experience where the person over‑screwed the tubing
arterial.They went on, went to sleep,
and through the night, there was a slow drip of blood that resulted in about a
unit of blood loss over a night.

We
have and Pierratos and everybody now has a water detection, moisture detection,
device, which I think should go under the kidneys or where it is or under the
kidney machine, which would alarm and prevent that from happening.

Once
again, that is human error and if the manufacturer can figure out a way that
when you anchor those lines in place there is a pop or something like
that.So the machines that are built
with cartridges or kind of packed in there, that decreases the number of
connections the patient has to make.

But
I think that a moisture detector device underneath the kidney would prevent
that.

CHAIRPERSON
TALAMINI:Great.Thank you.

Dr.
Moran?

DR.
MORAN:I think in view of the eloquence
of my colleagues, I should yield my 60 seconds.

CHAIRPERSON
TALAMINI:Thank you.

Dr
Blagg?

DR.
BLAGG:I would just like to comment
again on central monitoring because I'm pleased that Chris doesn't think it's
essential because I don't think it's essential at all.And many of the programs that are doing
nocturnal hemodialysis at this point in time do not use central monitoring.

I
think to have an internet connection so that you could download information as
to what happened during dialysis at a convenient time would be a nice addition
where it's available, but it's nothing essential.And in our program, we have one of the training nurses on call 24
hours a day to answer all patient questions.And we haven't seen any problems.So I don't favor central monitoring.

Another
point I would like to make is that there are state issues here, too.I was at a meeting recently where somebody
from Texas was explaining that for nocturnal hemodialysis in Texas, they're
supposed to take half‑hourly blood pressures throughout the dialysis,
which would certainly not help patients sleep.Apparently the Medicare surveyors in Texas will actually want to find
evidence that this is being done.So
there may be state regulations which may have different effects on some of
these things.

Thanks
very much.

CHAIRPERSON
TALAMINI:So we have already heard two
different opinions on central monitoring.Perhaps I could just get the temperature of the panel on that one issue.How many would favor central monitoring
being a requirement of such systems?

(No
response.)

DR.
GIBSON:Could we make that dependent on
whether the patient is alone or has a partner, which I think makes a big
difference?

CHAIRPERSON
TALAMINI:I don't want to make it too
complicated, but ‑‑

DR.
SCHULMAN:I think that's
essential.I think you should make that
difference.

CHAIRPERSON
TALAMINI:Okay.So let's say if the patient does have a
partner.How many think monitoring is ‑‑

DR.
WEINGER:Just to get more complicated,
are we assuming the partner is in the same bed or in some room at the other end
of the house?

CHAIRPERSON
TALAMINI: Present in the house.

DR.
WEINGER:Just in the house?

CHAIRPERSON
TALAMINI:Yes.So how many with that stipulation, a partner
present in the house, think central monitoring should be a requirement?

(Whereupon,
there was a show of hands.)

CHAIRPERSON
TALAMINI:Okay.Now, without a partner in the house, how
many think it should be a requirement?

(Whereupon,
there was a show of hands.)

CHAIRPERSON
TALAMINI:So I think there were six who
said yes to that.Okay.So, again, just a straw poll to get the
temperature of the group.

Dr.
Gillespie, you're ‑‑

DR.
LOCKRIDGE:Can I comment on the central
monitoring since the experience I have ‑‑ basically we have not
done central monitoring.I would like
to have ability to download it, but in those 41,000 treatments, we have not
identified a single event that central monitoring would impact on the safety of
the patients or the response time to the patients.And I think that is critical.

We
have a 24‑hour nurse on call that directly is called and talks to the
person.And we have 8 of our 33
patients at home dialyzing by themselves at home with nobody else in the home.

So
I'm saying that it appears to be safe, but I understand the viewpoint of the
panel.

CHAIRPERSON
TALAMINI:Thank you.

Dr.Gillespie?

DR.
GILLESPIE:Just a quick comment on
alarms.I think we have to think very
differently about alarms than we do in in‑center dialysis, where we have
alarms going off all the time, but because of the slow blood flow and slow
ultrafiltration rates, it's much less common.So it may not be as much a concern about disturbance of sleep and
everything.In the studies we were
given, they said there were an average of about one to two alarms a night.

I
think in patients after they kind of completed the initial training and got
used to it but certainly an important concern that we should look at when we
are evaluating these systems is, how often do they alarm?And what does that do to the patients'
sleep?

CHAIRPERSON
TALAMINI:Terrific.Thank you.

Dr.
Weinger, again I would offer you more than a minute and a half since so many of
these issues are human factor issues.

DR.
WEINGER:Well, thank you.Thank you for the comment on alarm.I don't have to say as much about that.So I'll just say that what alarms are
present need to have a high positive predictive value.

And
false alarms are almost as concerning as the absence of an alarm.In the presence of a false alarm, at best,
they're disruptive.At worst, they're
ignored or even disabled in some way that can impair safety.And alarms need to be designed and evaluated
on any device.And IEC 60601‑1‑8
is perhaps the best source for that.

More
generally, I want to talk about ‑‑ there's this whole section on
user‑friendly design here.And I
wanted to talk about that in a general way.And that is that ‑‑ and I know this point has been made, but
I think it's critical that useability testing is absolutely critical for these
devices.And it has to occur before the
clinical trials and, in fact, needs to occur throughout the design phase.

The
process results and documentation of the human factors engineering for the
device need to comply with current national and international standards, which
include ANSI AAMI HE 74, IEC 60601‑1‑6, and ISO IEC 62366.

The
final thing with regard to design is that there are a lot of questions later
about labeling and training, but I want to emphasize the importance of
designing the product right in the beginning to minimize the need for patients
to have training on how to attach all of these connections, on how to run the
session, on how to respond to alarms.

The
design should be sufficiently robust that errors are prevented wherever
possible, that when errors occur, that there is safe and easy recovery, that
when the device fails, it fails safe.And then you have issues of alarms.

The
other thing to think about we will talk about more is just‑in‑time
training, where, rather than just a beep going off, that the device provides
information about what is wrong and what one needs to do to fix it at the time
the event occurs.

And
I think I will stop there.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Gibson?

DR.
GIBSON:The only other thing I want to
add is that consideration should be given to having instructions displayed, not
just clearly in English but clearly in other languages.At least in New Orleans, we have many people
who might well benefit from this who do not speak English very well and don't
read English at all.

CHAIRPERSON
TALAMINI:Thank you, Dr. Gibson.

Dr.
Kalota?

DR.
KALOTA:Nothing more to add.

CHAIRPERSON
TALAMINI:Thanks.

Dr.
Aranoff?

DR.
ARANOFF:A couple of brief comments on
each section.When it comes to the
choice of blood access, that's going to have to be a medical decision based on
the physical characteristics of whether the patient can have a fistula conduit
or a catheter.And the devices should
be designed to function equally well with all three blood access, potential
blood access.

When
it comes to monitoring the blood access, redundancy has to be the key.However it is monitored, there have to be
redundant systems because it is inevitable that a blood disconnection will
occur at some time.And there must be
multiple system failure before someone exsanguinates.

Central
monitoring, whether or not it's mandatory or not, it should never be allowed to
be used as the only way of monitoring patients.

With
regard to user‑friendly design, Dr. Mendelson's talk could be used as a
check‑off list for the design of these devices.They should be as automated as possible.

They
should not be designed in a way that allows for use error.And patients should not be allowed to move
from one point of setup from treatment to cleanup without completing all of the
steps sequentially in order.

And
the devices should be designed in a way so that alarms or the appropriate
process cannot be short‑circuited, as they so frequently are in dialysis
units or in intensive care units.

CHAIRPERSON
TALAMINI:Terrific.Thank you, Dr. Aranoff.

Dr.
Afifi?

DR.
AFIFI:Yes.I would like to look at it from the point of view of a public
health professional.The concern I
think should be for taking the optimistic view that Dr. Blagg offered that this
could actually be better than existing current available technology.

I
hope this will be the case, in which case, though, what we want to pay special
attention to is something that Dr. Weinger said a minute ago.And that is, if the device fails, we want to
design it so that it fails safe.

And
that I think is a fundamental point from the point of view of looking at the
overall results when analyzed on a population‑based level that building
in the redundancy that Dr. Aranoff is something that perhaps the FDA could
think about requiring in some way.I
don't know what the actual implementation of that would be.

CHAIRPERSON
TALAMINI:Thank you, Dr. Afifi.

Dr.
Sadler?

DR.
SADLER:Two quick points.One of the items on here says, should we
justify leaving out standard alarms?I
would say no.The standard alarms are
good, and we need them.

Secondly,
the blood access is the greatest source of anxiety and the greatest opportunity
for improvement.This is the one place
where a central catheter without needle access would be desirable.And if product development is going to take
place, a central catheter that is more securely attached less prone to
thrombosis and infection would be an advantage.

CHAIRPERSON
TALAMINI:Just prerogative of the chair
here, does anyone disagree with Dr. Sadler with regard to point G,
justification for leaving out any standard alarms or features found in
traditional equipment, just so we can be clear on that point?Dr. Lockridge?

DR.
LOCKRIDGE:Yes.I think the traditional alarms, there's so
much that has been on a dialysis machine:sodium modeling; conductivity; Kt/V, which has become standard
modeling.All of that stuff needs to
go.It needs to be very simple for the
patient.And that's built into a lot of
alarms there.So that needs to go.

But
as far as the standard alarms, we need to keep them.

CHAIRPERSON
TALAMINI:Any other comments on leaving
out alarms?Dr. Hoy?

DR.
HOY:Our patients don't have a problem
with the alarms.We only have about 1.3
alarms per patient per night.What they
have a problem with is that sometimes they're more sensitive than they need to
be.And specifically for a catheter,
they would like a longer time before the alarm goes off.And for a fistula, we would like a shorter
time before it goes off.

So
we would like some variability built in that allows us to set the alarms to go
off dependent on the access.

CHAIRPERSON
TALAMINI:Great comment.

Dr.
Lockridge?

DR.
LOCKRIDGE:The other issue that we
found in training, hearing is a big issue as you get older.And none of the machines are designed to
deal with a hearing deficit.We have
developed a vibrating connector to the machine that vibrates and puts under the
pillow.

So
I think technology is out there.The
manufacturers need to look at that to deal with hearing deficit.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Weinger?

DR.
WEINGER:Just like any other feature on
these future devices, the alarms that are chosen need to be tested in the end
users.And so one can vote in favor, as
I would, of retaining alarmable conditions, but the specific alarms and how
they are triggered and what they sound like probably will be very different for
a home device than for a device in a dialysis unit.

CHAIRPERSON
TALAMINI:Dr. Hoy?

DR.
HOY:One last comment.When we asked our patients how they would
approve the alarms, some of them have already done it.We use a Fresenius 2008H machine, which has
buttons, not a touch screen.And they
have put tactile felt or something else on the buttons to identify the ones
that most commonly go off, the arterial pressure button, so they can reach out
and just shut it off as they turn over and go back to sleep.

Tactile
probably is helpful, not useful with a touch screen.

CHAIRPERSON
TALAMINI:Great.Thank you.Those are great comments.

Dr.
Schulman?

DR.
SCHULMAN:Well, I would also agree with
Dr. Sadler that the most worrisome issue is worrying about a blood
disconnect.And I think that to the
extent that the manufacturers can provide us with a way to have these
safeguards be set so that the machine can't, the patient can't be treated
unless their force should be an important feature of design.

Secondly,
I think I would like to know about the quality of the treatment.So in central monitoring, I think you can
have a memory stick with a USB port on the machine to capture it with the
parameters of the treatment, including things like Kt/V, that could be brought
in for review periodically.

CHAIRPERSON
TALAMINI:Thank you, Dr. Schulman.

Dr.
Duffell?

DR.
DUFFELL:I'll pass.

CHAIRPERSON
TALAMINI:Ms. Moore?

(No
response.)

CHAIRPERSON
TALAMINI:That is terrific.Great job.We did that in 20 minutes.

So
just a couple of other issues.I don't
think anybody discussed specifically point C in central monitoring, and that is
software as involved with central monitoring.

Do
any of the panel members have a specific comment with regard to software?Dr. Lockridge?

DR.
LOCKRIDGE:Yes.I think that the point about bringing in and
clinically monitoring these people, if you could have the machine designed to
be able to just take a phone line and plug it in, hit a button, and it dials up
and downloads the stuff to my computer in the home training area, then I can
monitor each treatment each day, the nurse can, and look at that.

The
other thing is central monitoring is critically ‑‑ in my
population, I looked at it.Forty
percent of the people that I've sent home could not afford two lines of
internet connection.So when we
basically create a central monitoring, we're going to select out the people,
the haves and the have nots.And that
is not who is doing dialysis.

So
I think we have to figure out a way to not do that.

CHAIRPERSON
TALAMINI:Dr. Hoy?

DR.
HOY:A comment on this issue of the software.This is done very differently all over the
world.About half of the units that are
doing nocturnal dialysis in the world are doing monitoring.Let me take that back.It's about a third of the units, but they
constitute half of the patients.

For
example, in Holland, their monitor, their observer, is Lifeline.They find so few alarms and so few problems
that they outsource it to Lifeline.They use people who are not trained in any way, shape, or form to know
anything about dialysis.

In
Toronto, Dr. Pierratos brings people in off the street who have no contact at
all with dialysis and trains them to be the observers.

This
isn't rocket science.It really is safe
to do.And you can do it.And you can have a set of protocols that
allow us to know when to call the nurse on call, when to call the doctor on
call, when to call the technician on call, and how to intervene.

So
that there are definitely software that is useful.Fresenius has come up with a wonderful system called
Eyecare.There is another system out
there by Sebernius, which is what we use.These are very good systems.They're not perfect, but they work.And then you have protocols which are implemented by the people
watching.

CHAIRPERSON
TALAMINI:Let me do Dr. Blagg
first.Then I will come around to Dr.
Sadler.Dr. Blagg?

DR.
BLAGG:A couple of quick comments.If you actually use central monitoring and
add it to the cost of the treatment process ‑‑ and that may be a
concern ‑‑ the same thing is that Dr. Pierratos does not feel that
remote monitoring is essential to all.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Sadler and then ‑‑

DR.
SADLER:I just wanted to make the point
that among the issues we raise, this is of interest, but this is secondary to
the more important ones.

CHAIRPERSON
TALAMINI:Dr. Aranoff?

DR.
ARANOFF:We're actually talking about
two aspects of monitoring here.One is
the safety of the treatment.And the
other one is to access clinical information about adequacy and the
characteristics of the dialysis treatment.

My
comments about safety and monitoring are that we should never use central
monitoring as the only way of monitoring safety.And others have recognized that it may not be necessary at all.

And,
secondly, I would point out that the majority of home hemodialysis or
peritoneal treatments now done in the United States do not download information
to any central source.And, in fact,
the vast majority of in‑center hemodialysis treatments provided in the
United States do not download this information electronically to any central
source.

CHAIRPERSON
TALAMINI:Terrific.

Dr.
Kalota?

DR.
KALOTA:He answered my question.

CHAIRPERSON
TALAMINI:Okay.I would just like to ask the FDA ‑‑
this might be a spring on these folks ‑‑ if there are other issues
that the panel had either missed or that you would like us discuss in more
depth with respect to device designs.

MS.
BROGDON:Thank you.I was checking with the staff on that
question.And Dr. Ruiz would like to
ask something.

CHAIRPERSON
TALAMINI:Okay.Dr. Ruiz, please?

DR.
RUIZ‑ZACHAREK:And I'll be very
quick, too.This question is for Dr.
Hoy.You said that partners are not
required among your patient population.You reported also some patients that have some serious events, not
treatment‑related but basically a kidney rupture, which is pretty danger
and you need to act quickly on it.

What
would happen if there is no central monitoring, no partner, and someone who
lives far away?In the cases that you
presented, emergency personnel showed up in 15 minutes.If these patients live in remote areas, what
type of safeguard would we have or should we restrict the nocturnal dialysis to
patients who live close to hospitals?How would we address patients that live far away?

DR.
HOY:This is a perfect technique for
people who live far away from a dialysis unit in a hospital.If a catastrophic event takes place in an in‑center
dialysis unit and the emergency squad gets there in 15 minutes, which is about
what it takes, it doesn't change the outcome most of the time.

Those
events, we have incredibly sick patients, you know, and they die.And they die suddenly sometimes.The fact that we have had a mixed bag, we
had one patient die, despite the observer, the partner, and emergency response
quickly.We had one patient whose life
was probably saved by the observer and the rapid emergency response.

We
send out a video to the emergency squad for every patient.And we have the number of that emergency
squad.And that video shows them, this
machine, and how to disconnect it because that is all they need to know.

If
the patient has a partner who wants to learn how to do this, we teach the
partner to do it.But the main reason
that there are only 98 people in New York State on home hemodialysis out of
20,000 and less than 1,000 in the entire country is because of care‑giver
burnout.

CHAIRPERSON
TALAMINI:So would you contend, then,
that the emergency response system of the country in general as it exists is
already sufficient for whatever would happen with this population?It sounds like that is what you are saying?

DR.
HOY:Yes.I don't think this population is any different than any other
population that's at home and sick or in center and sick.

DR.
SADLER:I simply refer to my earlier
remarks about passive restraint levels of safety.There are some things you cannot guarantee.The worst thing that can happen to one of
these patients is not to get his dialysis.

So
that to be remote from a hospital and a dialysis center and to have the ability
to get it done at home without having to travel, it may involve some risk, but
it avoids that very large risk.

DR.
RUIZ‑ZACHAREK:Thank you.

CHAIRPERSON
TALAMINI:Dr. Duffell?

DR.
DUFFELL:Similar to the last comment, I
just think FDA needs to keep in mind that we really can't regulate totally the
use of these things.I mean, clinical
judgment has to come into play here.Patients are very complicated.So there may be extenuating circumstances.

I
think the most you can do is probably in the professional labeling give the
benefit of the wisdom of the things that you see in MDR reports and complaints
and stuff that come through of points to consider.But the clinical judgment has to come into play.

So
if that patient is 100 miles away from an emergency response team, there may
still be compelling reasons to do this.

CHAIRPERSON
TALAMINI:Yes?

DR.
BLAGG:Just one rapid comment.Patients may go home with a helper, but the
helper may not stay around.And, for
example, our patient with an IQ of 87, measured by a psychologist, not by me,
we didn't find out until he was transplanted that for the last 15 months, his
roommate had not been with him.He had
been dialyzing alone very successfully.

So
we can't control that the helper stays there.

CHAIRPERSON
TALAMINI:Yes.Thank you.

So
that will close question one.

DR.
LOCKRIDGE:There is the issue about the
water I don't think we really addressed.That is in this section.I think
as far as design purposes for the machine, I think AAMI standards are very
critical and we need to be able to have a patient‑friendly port that
looks at the water post ‑‑

CHAIRPERSON
TALAMINI:That is actually question
two.

DR.
LOCKRIDGE:I'm sorry.

CHAIRPERSON
TALAMINI:So we're about to get to
that.So let me be the ugly surgeon and
get you guys to do one more question before we break for lunch.So if we could do question two, which refers
to device design with respect to water?

"The
quality of the water to be used to prepare dialysate is crucial for any
dialysis treatment.Please discuss the
water purification needs for the NHD procedures, including the following:a) type of water treatment equipment for
preparation of water and verification of its quality appropriate for nocturnal
home use; b) due to the potentially higher exposure of patients to the
processed water, consideration as to whether the water quality recommendations
should be different for nocturnal home use, as opposed to conventional, in‑clinic
use; and c) procedures on how to handle changes in the water quality and
composition by municipal water suppliers.

Dr.
Lockridge, since you have started in, go ahead.

DR.
LOCKRIDGE:All right.I think water deals with 60 percent of the
problems that I have with the patient at home.I think it is a major issue that we have to address.I think we have to meet the AAMI
standards.And I think that if we do
that, that is where we need to be.

Clearly,
I think whether we choose to do an RO versus a DI is not the issue.I think what we do need to have is the
highest quality water because these people are seeing more water per week than
they are when they are doing three times a week in‑center dialysis.

There
needs to be, you know, the carbon filter, a pre‑filter that protects the
sediment that gets into the water, well water, before the carbon tank, the
carbon tank to do with the chloramines, and then a post‑DI or if you use
DI microfilter.And then you need to
have another filter to do the dialysate or to create ultra‑pure water, I
think.

So
I think that we need easy ports for the patients to access the water at each
one of those points so that we can test the water so it meets AAMI standards
and the clear CMS requirements once a month for colony counts and LALs and how
often we need to look at the dialysate.

So
I think it's critical, easy for patient to access.We're not going to send technicians to go out and do that.We need the design to do that.

CHAIRPERSON
TALAMINI:Terrific.

Dr.
Moran?

DR.
MORAN:I think the new AAMI standards
have it specifically the same for in‑center and home use.And I would agree with that.I think I disagree about the concern about
the potentially higher exposure of patients to processed water.I think if they make the AAMI standards,
that should be fine.

Procedures
how to handle changes to the water quality, that's a never‑ending saga,
both for centers and for home patients.And it's one of the biggest things we struggle with at home.

We
have to have redundancy in the system.That's why we have two carbon tanks.They're testing the water between the two carbon tanks.And when the first carbon tank shows
evidence of a breakthrough, then they change that tank.It's a fail‑safe system, but it is a
big issue.

One
of the concerns I have about AAMI is saying that the water should be tested
once a month at home.That's much more
difficult to do than it is in center, especially for some of the machines.I think at home, where you are dealing with
a single established system which doesn't have storage tanks, as you do in
center, no blind loops, as you do in center, there is much less risk of water
problems.And, therefore, the testing
should be done at some period less than once a month.

CHAIRPERSON
TALAMINI:Terrific.Thank you.

Dr.
Blagg?

DR.
BLAGG:Just a brief comment, following
up on Bob.I think that there is a
tendency to move towards ultra‑pure water for dialysate, particularly in
Europe but coming in this country, too.And it's something that we should think about.

I
agree with Dr. Moran that it is very difficult.The way we handle our home patients is we try to contact the
local water company, wherever they may live, every six months and also make
sure that they know our phone number.But it's a problem you can't always solve.

CHAIRPERSON
TALAMINI:Thank you, Dr. Blagg.

Dr.
Gillespie?

DR.
GILLESPIE:I think I'll pass and defer to
my colleagues on this.

CHAIRPERSON
TALAMINI:Thanks.

Dr.
Weinger?

DR.
WEINGER:Just a general comment.To the extent that patients have processes,
procedures, and devices related to water purification and assessment, those
need to be designed for patients and evaluated for their ability to use them
effectively.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Gibson?

DR.
GIBSON:Yes.This is more in the nature of a question for those of you who
know more than I now do about the technical aspects of hemodialysis since I
haven't taken a dialyzer apart or set up a water treatment system in a long
time.

But
it used to be at least theoretically possible for back diffusion to occur in a
high‑flux system.And by that, of
course, I mean dialysate passing into the blood compartment.

So
my question is, is that a real possibility?And would that make a difference in your view of whether AAMI's
standards are essential or whether we should recommend ultra‑pure water?

CHAIRPERSON
TALAMINI:Dr. Sadler, do you want to
address that?

DR.
SADLER:I don't think there's any
question but that back diffusion occurs in dialyzers.And I don't think there's any evidence that it's harmful.And, as I said before, I am still waiting
for any evidence that anyone is harmed by water that meets AAMI standards, even
the original AAMI standards.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Kalota?

DR.
KALOTA:Pass.

CHAIRPERSON
TALAMINI:Dr. Aranoff?

DR.
ARANOFF:Just a couple of brief things
about water.First of all, I agree with
my colleagues that there is no evidence that water that meets the AAMI standard
would be inadequate in any way for this form of therapy.

However,
with regards to the increased amount of ultra‑pure water that is
processed, we need to make sure that the home systems that are used are capable
of handling the increased volume for the creation of dialysate that may not be
considered.You're running a lot more
water through the systems.

And
so issues of number of hours on the device, issues of preventative maintenance
and so forth, those issues need to be considered in the use of the device
because they may need to be done more frequently than we are used to than with
current home devices.

And,
again, with regards to procedures to handle water quality from municipal
systems, many of our home patients live in very rural areas.If they have city water at all, the people
who make that city water may not be as highly trained as in larger cities.And they have a tendency to dump things into
the water to make it taste better or clearer.

And
there needs to be some way of monitoring when alum is dumped in to take out
particulates, when chloramines rise and may foul the carbon tanks.And so that needs to be monitored, I think,
as Dr. Lockridge pointed out.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Afifi?

DR.
AFIFI:No comment.

CHAIRPERSON
TALAMINI:Dr. Sadler, further comments?

DR.
SADLER:Only two.One, we need to remember that the AAMI
standard is a performance standard.It's not a prescriptive standard that says, "Thou shalt use"
this device or that but that the water should come out meeting the standard.

I
agree completely with Dr. Weinger that we haven't thought enough about the
displays on water treatment systems for the benefit of patients and that should
be considered.

And
beyond that, nothing except to remind you that a private well doesn't have to
worry about a municipal operator fouling it up.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Schulman?

DR.
SCHULMAN:Most of what I thought of has
been said already, but just for completeness, I would add that for the areas
that have hard water or water softener should be part of the water treatment.

CHAIRPERSON
TALAMINI:Okay.Dr. Duffell?

DR.
DUFFELL:I'll pass.

CHAIRPERSON
TALAMINI:Ms. Moore?

MS.
MOORE:Pass.

CHAIRPERSON
TALAMINI:Dr. Hoy?

DR.
HOY:As usual, I have a lot to
say.We have had a lot of different
experiences with different water sources.Several of our patients are in rural areas.And we have discovered that if you are downstream, if your
aquifer is downstream, of agricultural lands, there are real issues with
increased phosphates when people are fertilizing and when there is a lot of
rain.

We
also have problems with droughts.And
so patients have had to come in center for that.We have also had people who were downhill of somebody else's
septic system.Their well was downhill
with someone else's septic system.These are real problems, but we have managed to settle all of them when
we need to.

We
have urban systems that are old with a lot of particulate matter.You have to have pre‑filters.We do water softeners and carbon
filters.We use ROs because they are
less expensive and they're less cumbersome and bulky.

We
have had problems with suburban homes with patients getting constantly
reinfected.And it turned out that the
home itself had E. coli infection and other gram‑negative bacteria in the
piping of the system.We had to shock
the whole house to get rid of the problem.

The
supply, especially for ROs, needs to be more efficient.You throw away half of the water we use in
RO.We want to get up to the industrial
efficiencies, where 75 percent is recovered for dialysis.

You
have a problem with the adequacy of septic systems for effluent.You're dumping a lot of water every day into
a septic system.You often need a
larger drainage tank.There is an
ongoing cost, increased cost, to the patient of water, though in our area, it's
not huge.

Reverse
osmosis machines if they have stagnant loops often get contamination.And they need to be designed so that water
is always flowing between the dialysis machine and the RO.

Incorrectly
collected cultures are the bane of our existence.In our unit in March, five patients had to be treated in center
for at least one dialysis and in April, four patients.And half of those were because of incorrect
or because of falsely positive cultures.

Our
patients point out that they cannot collect the cultures if there is an open
window, a fan, or a ventilation system going on in the room at the time they
collect them.It would be very nice to
have what Bob suggested, which is an easy port through which those cultures can
be collected safely and cleanly because it a huge inconvenience to the patients
to have to go in center while we are waiting for cultures to come back and be
proven to be incorrect.

The
new AAMI standards don't worry me particularly.I think the issue of ultra‑pure water is a problem that you
should be addressing for all dialysis patients.If you told someone that you were exposing them to two liters of
water a day that they drank and then you told them that you were exposing them
to 576 liters of dialysis weekly because they go to dialysis 3 times a week for
4 hours and then have a dialysate flow rate of 800 cc, you wouldn't even worry
about whether the 1,400 liters that we expose our nocturnal patients to is an
issue.

I
think you need to address the issue of ultra‑pure water for all of our
dialysis patients.And you don't require
it for our in center patients, and we should probably.

Maintenance
of ROs is incredibly cumbersome.They
should be made simpler.They should
have timers.They should have
automation.They should be online so
that we can download preventive maintenance.They're not reliable.They need
to be more reliable.

DI
tanks we find give more efficient water use, but they're more expensive over
the long run.They do have lower
maintenance.They're bulky, and they
have to be replaced every three months.

CHAIRPERSON
TALAMINI:Thanks.

Dr.
Weinger, would you be willing to address a human performance way to help the
false positive culture problem?

DR.
WEINGER:I'm not sure I fully
understand it, but what I think I heard from one of you was the idea of having
this dedicated port.And certainly if
this is critical to the success of the overall treatment, then that ought to be
part of the waster component, needs to be part of the overall system.And built into that should be a mechanism to
take the cultures easily and effectively as necessary.

I
think that I have a general comment, if I could, at this point ‑‑

CHAIRPERSON
TALAMINI:Sure.

DR.
WEINGER:‑‑ about the fact
that what we see with other medical devices, whether it's in the home but even
in the hospital, is that when the functions that need to be accomplished
require multiple components, particularly if they are manufactured by different
companies, the risk of use there and injury increases substantially, probably
exponentially.

And
so something to think about is whether home systems need to be a comprehensive
integrated system that includes the monitors, the water treatment, et cetera,
all as one unit, rather than the ability or the obligation, as happens now,
where the practitioners are cobbling together devices and solutions from
multiple sources, which I think substantially increases the risk.

CHAIRPERSON
TALAMINI:Thank you.

Let
me just try and get again the temperature of the committee with respect to
question B here because it sounds like there have been slightly different
opinions.And that is whether water
quality recommendations should be different for nocturnal home use, as opposed
to conventional.

I
think I heard mostly a no.So I'll ask
the opposing question.Is there anybody
who thinks that they indeed should be different for nocturnal home use.A show of hands, anybody who thinks they
should be different?

DR.
HOY:Dr. Talamini, do you want the
consultants to vote or not?

CHAIRPERSON
TALAMINI:You know, I don't think it
much matters here because we are really just getting the opinion of this
committee.It's not an official
vote.So don't think ‑‑

DR.
SADLER:Dr. Talamini?

CHAIRPERSON
TALAMINI:Yes, sir?

DR.
SADLER:When we go from normal kidney
function to dialysis, we increase water exposure 200‑fold.

CHAIRPERSON
TALAMINI:Right.

DR.
SADLER:When we go from conventional
dialysis to frequent nocturnal dialysis, we double it again.So that's not an order of magnitude, and I
don't think the difference is significant.

CHAIRPERSON
TALAMINI:Thank you.

I
would ask the FDA again if there are other issues you would like the panel to
address specifically on this question before we close the question.Yes, sir?

DR.
MENDELSON:I have a question.This doesn't pertain directly to human
factors but just a thought.Does the
presence of plastic piping, which is probably more prevalent in the home, place
a higher bacterial load on the filtration equipment that is going to be used to
treat the water?

CHAIRPERSON
TALAMINI:Any panel members have
insight or response?

DR.
LOCKRIDGE:You know, you're talking
about microfilming that happens in plastic, but I just think that that is
probably not an issue for the amount of water that runs.I just can't ‑‑

DR.
ARANOFF:Functionally in dialysis
units, all of the piping is plastic in dialysis units.We have to use PVC piping.Otherwise, ultra‑pure water will etch
metal pipe.So every fitting, every
pipe in a dialysis unit is already plastic.

CHAIRPERSON
TALAMINI:Okay.Perfect.

Any
further questions from the FDA?Yes?

MS.
MOORE:I have a question.I just have a question based on the last
comment that was made.

CHAIRPERSON
TALAMINI:Ms. Moore, if you could just
bring the microphone in?Thank you.

MS.
MOORE:I have a question just on your
last comment.Does that mean that the
old houses, you know, with still the copper piping and that kind of things,
there would have to be a change or something?

DR.
ARANOFF:No.The difference is that in a dialysis unit, you process the water
before the dialysis unit.So, actually,
what is delivered to the dialysis unit is essentially ion‑free ultra‑pure
water to be mixed into dialysate at the machine.

So
from the point that the water is purified in the dialysis unit in the basement
or on the ceiling or on the roof, wherever, from that point on, it has to go
through plastic piping.

In
a home, in a home setting, the water is purified closer to the machine.But from the point, that point on, it has to
be plastic piping.

CHAIRPERSON
TALAMINI:Dr. Neuland?

DR.
NEULAND:Yes.I still need a little bit more clarification on the views on the
ultra‑pure water because your question, Dr. Talamini, was, do you think
that the systems in the homes should be different than the clinic?But I heard a number of people here say,
"I think ultra‑pure water should be used, and then it should also be
used in the clinic."

So,
I mean, I'm not getting a good picture on whether you really believe ultra‑pure
water should be used in the nocturnal home hemodialysis.I mean, I feel like we have kind of evaded
the exact question.

CHAIRPERSON
TALAMINI:Well, I think this panel is
unwilling to say that there is a difference between the two.But I think it would be fair enough to ask
for the temperature of the committee with respect to that question, whether
overall ultra‑pure water should be used in dialysis, period.

Is
that fair enough?Can I ask the panel
that?Dr. Lockridge, do you have a
better suggestion or ‑‑

DR.
LOCKRIDGE:No.You know, I think that the literature from
Europe and some literature now that is coming out here would suggest that ultra‑pure
water is better, that we're looking at more of an inflammatory marker, but I
agree with when you're looking at 1,000 patients versus 300,000 patients and
trying to make a difference when it's just a twofold difference, I would hope
that the designers or the manufacturers would have what we call a dialysate
filter before their filter or they're using columns to remove it to make it
ultra pure.

I
would think that would be a goal, but if FDA requires it for home patients to
be a goal, then I think that is inappropriate unless they are going to require
it for in center.

CHAIRPERSON
TALAMINI:Dr. Gillespie?

DR.
GILLESPIE:I think this is still a
developing field of research.I mean,
intuitively cleaner water sounds better, but we still haven't totally figured
out how it plays out clinically.And we
also have to consider when we're talking about outcomes that I think most of us
would agree that more frequent dialysis has a tremendous effect on
outcomes.That's kind of the big
picture.

And
so issues about the water purity are probably just the detail that may not have
as much of an effect as just the transition from less frequent to more frequent
dialysis.

DR.
SADLER:I think I have already made it
clear that I believe the increase in the quality of water, the standards
reached for have nothing to do with the treat to patients that we can
define.It has to do with the fact that
we are capable of making a higher quality of water.

There
is indeed some literature that says perhaps there will be a lesser inflammatory
response with ultra‑pure water, but I don't think that data is anything
like strong enough to change the practices across the field.And I think we have to be cautious about
requiring things for which there is no clear need.

You
know, this is a group that is a mixture of zealots and skeptics.And so we're always going to have
differences.

CHAIRPERSON
TALAMINI:Right.We'll take a one‑hour lunch break at
this point.I would like to thank the
panel for really terrific work and concise comments.And hopefully we'll be able to continue the same.

Yes,
Dr. Duffell?

DR.
DUFFELL:Just to the audience in my
role as industry rep, if there are any members of industries out there that
have any matters that are going to be discussed with the panel today that you
would want to discuss with me, please approach me during lunch.Thank you.

CHAIRPERSON
TALAMINI:And I would remind the panel
again that this is an open proceeding.So may not discuss any of these issues that are before the panel during
lunch.So I would ask you to be
disciplined.

So
we will reconvene at 1:46.Thank you.

(Whereupon,
at 12:46 p.m., the foregoing matter was recessed for lunch, to reconvene at
1:30 p.m. the same day.)

A‑F‑T‑E‑R‑N‑O‑O‑NS‑E‑S‑S‑I‑O‑N

(1:48
p.m.)

CHAIRPERSON
TALAMINI:I think we will go ahead and
reconvene the panel at this time, again in the interest of getting done in a
timely manner.So the meeting now
reconvenes with the continuing panel discussion portion of the meeting.And we will begin with the third
question.So far the processes seem to
work well.So we'll stick with it.

Question
number 3 has to do with risk analysis.FDA has identified the following potential risks associated with NHD, in
addition to those related to conventional hemodialysis:a) increased risk of inadvertent
disconnections, the increased blood loss from increased frequency of
treatments, c) potential increased rate of vascular access infection due to
increased use of access, and d) psychological effects; e.g., impact of
treatments on patients, such as loss of social interaction, and the impact of
increased responsibility on the patient, requiring need for adjustment or
discontinuation of therapy.

To
aid FDA in the development of a guidance document on NHD, please comment on the
completeness and appropriateness of this list.I think we left off with Dr. Moran if you're willing to pick a piece of
that and comment for a minute and a half.

Again,
I would applaud the Committee on their clarity and brevity this morning.And if we could continue to push that, we'll
make the taxis and so forth, the flights this afternoon.

Dr.
Moran?

DR.
MORAN:I think this is a very good
list.I agree that the risk of
disconnection is the single most serious problem we should be dealing with with
nocturnal hemodialysis.And that has to
be addressed, whether it's catheters, as Dr. Sadler wants to do, or with
fistulas and button holders I want to do with precautions against disconnect.

I
agree it's a very serious issue.I
think technically the best answer to that would be a single needle technique,
either a dual/single needle or a machine that is providing a single needle.

Increased
blood loss, I can see that that occurs.I don't think it is an issue in the age of intravenous iron and
erythropoietin.I think the benefits of
frequent dialysis far outweigh this risk.And conventionally most people find that erythropoietin usage actually
goes down with nocturnal hemodialysis.

Vascular
access infection, I would make one point.In our home patients using the button hole techniques six times a week,
we have had two serious episodes of staph aureus septicemia in young men with
fistulas using the button hole technique.And I can't remember the last time I saw staph aureus septicemia with a
fistula.

We
know there was a break in technique from one patient.We know the other patient was doing things like dialyzing himself
at 3:00 a.m. and probably, therefore, careless.We have since then very strongly emphasized skin prep and haven't
had any more problems.

But
the button hole technique is wonderful.The patients love it.But I
would caution about the increased risk of infection.

Psychological
effects.I don't see those.The psychological effect I think you have to
be careful about is the partner.I
think it's like living related donor transplantation.You have to take the partner aside and make sure the partner
understands what they are committing to and make sure that they have a real
commitment, they're not just saying yes because they don't know how to say
no.I think that is a major issue.

I
think that is the end of my comments.

CHAIRPERSON
TALAMINI:Okay.Thank you, Dr. Moran.

Dr.
Blagg?

DR.
BLAGG:I agree with all that has been
said.I think the bit I would add is
that our experience at least has been that vascular access problems of all
sorts are not increased with more frequent sticks and that this reflects the
fact that the patient or one other person is doing all of the sticks, rather
than the 20 people that somebody mentioned a little while ago.

And
in terms of the psychological effect, we still try to persuade the patient to
do as much themselves.And in our
program, about two‑thirds of the home patients, the patient is the prime
mover and does most of everything or everything, but psychological problems do
occur from time to time obviously.

The
second patient that we trained in Seattle should have been divorced.Unfortunately, the patient died, but it
really destroyed his marriage.And that
made us aware of these things very early on.

CHAIRPERSON
TALAMINI:Thank you.Dr. Gillespie?

DR.
GILLESPIE:I agree with all the
preceding.I would just add that on
item C for the potential increased rate of vascular access infection, I would
broaden that to just any vascular access complications because if you are
worried about potentially thrombosis or other failures resulting from increased
use.And, of course, the literature
hasn't really borne that out, but if you're looking at risk, that would be what
you would want to consider, I think.

CHAIRPERSON
TALAMINI:Okay.Dr. Weinger?

DR.
WEINGER:One item that isn't on here
that we have mentioned before is acute decreases in water quality, for whatever
reason.In terms of useability issues, I
would add to the list risks of misconnection, particularly related to
disposable components, issues related to family, friends, pets, and other
entities in the environment interacting with the device, and then the general
issue of response to abnormal conditions and either a failure to respond or an
inadequate or inappropriate response to emergency or just atypical condition.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Gibson?

DR.
GIBSON:Well, I'm glad to see
psychological effects on the list at all.In terms of adaptation to chronic illness, there is much more that we
don't know than we do know in terms of how people cope with the stress of
chronic illness.

As
I said before, I think that there are some potential benefits to home dialysis
that need to be considered along with the risk.And those benefits would be a sense of mastery that increases
self‑esteem and psychological well‑being.And I don't think that is trivial.

I
think other people have already emphasized another aspect of this that is extremely
important.And that is if negative
effects are seen, it is more likely to be on the family, rather than on the
receiver of the dialysis solely.

Now,
I think that was shown beyond any question.And what limited data is available from studies of conventional home
hemodialysis and peritoneal dialysis is that care‑giver burnout, which
someone has already mentioned, is one of the more significant negative aspects,
negative psychological aspects, of dialysis.

And
it's not just limited to the care‑giving partner, but it involves the
whole family in new ways of learning social interaction and new ways of
scheduling activities and new limitations on things that they can no longer do
that they used to do.

Now,
I don't think any of these are reasons for the FDA to not approve this as a
method.As I've said before, these are
things that we don't know the answers to on conventional dialysis.And the purpose, as I understand it, of our
meeting here is to determine safety and effectiveness, not to determine long‑term
effects.

So
I do not like to see us use psychological exclusions, arbitrary psychological
exclusions, as reasons not to put people on nocturnal hemodialysis.I was very impressed with what Dr. Hoy said
earlier, which was that the main determinant of who can go on nocturnal
dialysis is a person's motivation for doing it.

I
don't think psychiatrists are able to predict with any degree of accuracy who
is smart enough and adept enough and intellectually aware enough to do this
successfully over the long term.

CHAIRPERSON
TALAMINI:Thank you.

Perhaps
to add a little bit of clarity, it seems ‑‑ and anybody can correct
me if I am wrong on this ‑‑ the key question here is whether any of
these four or any that aren't on this list represent incremental or additional
risk for nocturnal home dialysis, as opposed to dialysis as it's now practiced.

So
it sounds like we've got a set of comments from the beginning folks on all of
these issues, but as you think about this question, I think that is the real
thing we need to get at is whether the FDA has to be concerned about
incremental risk with doing this at home, as opposed to the way it is currently
practiced.

DR.
ARANOFF:I think to address that
specific question is that the incremental risk is related to the incremental
number of treatments and the time that are incrementally increased on dialysis.All of these things could happen in
conventional hemodialysis.

I
would also like to point out that we probably need to give some consideration
to risk analysis of the problem of unintended consequences of this therapy.

So,
for example, we have identified the potential unintended consequence of
worsening of anemia because there is a defined amount of blood loss with each
treatment.And is that overcome by the
better management of uremia per se?And
that is a question to be answered.

We
have also identified the unintended consequence of abnormal electrolyte values
because there's increased dialysis exposure, but there may be other unintended
consequences.

So,
for example, although some of the group favor the use of catheters for this
procedure, there are others who would passionately argue that catheters are not
a good dialysis access for anyone for other reasons, because of plastic and
inflammation and the body of evidence for that.So perhaps there ought to be some consideration that ensures that
all access devices would be useable for this form of therapy.

And,
finally, other unintended consequences on things like drug clearance, the
dosing of drugs in patients that are getting vastly increased clearances of
small molecules, the dosing of the drugs, and those recommendations will need
to be considered as well.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Afifi?

DR.
AFIFI:Yes.There's a close connection between this question and the next
one, which is study design.Specifically, risk analysis should be I think, partially at least, aimed
at identifying how analyzing the potential risks can help us avoid adverse
events.

And
also in my mind from a statistical point of view, we need to classify the risks
and the adverse events later when we get to them as to whether they are life‑threatening
or not because the kind of thinking I'm sure from the clinical point of view,
but what I know more about is from the statistical analysis point of view, the
analytical approach would be different for a life‑threatening event
versus a non‑life‑threatening event.

So
these issues I think are ones that need to be clarified.And the connection between this question and
the next I advise FDA to think about and spell out more clearly.

CHAIRPERSON
TALAMINI:Okay.Thank you.

Dr.
Sadler?

DR.
SADLER:I have to say that these
potential risks are presumptive, rather than demonstrated.And I believe that they are itemized because
of the potential for a worse outcome if they happen than if they happen in the
presence of a number of other people.

And
so it would be very important to tabulate these events because I rather doubt
that they happen more frequently in this form of dialysis than anywhere
else.They might actually happen less
often because there will be more consistent procedure by people who have more
motivation to do it right.

I
guess I have to correct George, Dr. Aranoff.I did not say that I supported increased use of central catheters but
simply that because there are benefits of them in this environment, we should
see if we couldn't improve that device or we should hope that someone would try
to improve it because I suspect we will always need some.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Schulman?

DR.
SCHULMAN:We'll be at the end of the
line here.Most of what I thought about
has been said already.However, unless
and until devices to prevent disconnection occurring at nocturnal dialysis,
that is something that probably we have to be concerned about as above the
standard dialysis treatment.

CHAIRPERSON
TALAMINI:Okay.Thank you.

Dr.
Duffell?

DR.
DUFFELL:Like Dr. Afifi, I am drawing a
connection with this risk analysis to the next question, which is study
design.And I guess the cautionary
remark I would make is that some of these things, especially when you're
talking about infection rate or psychological effects, are probably long‑term
assessments that have to be made and probably not something that you would want
to force on a manufacturer to do in a prospective trial prior to approval of
these technologies to go out.

So,
in other words, I think they are probably more of an issue for post‑market
surveillance, rather than a prospective study to get to market.

CHAIRPERSON
TALAMINI:Thank you.

Ms.
Moore, pass.Dr. Hoy?

DR.
HOY:I don't think that we're seeing
disconnections at the patient's access.However, we've done about 27,000 treatments, and Dr. Lockridge has done
41,000 treatments.And both of us have
seen a patient inadvertently either cross‑‑thread or over‑exuberantly
tighten the blood connection at the dialyzer.

And
my patient slowly lost blood until he woke up in the middle of the night.And the blood dripped down the tubing and
fell away from our moisture protector underneath the machine.

So
we've both seen the potential for a very strong person in this case to mis‑cross‑thread
the connection at the dialyzer.

CHAIRPERSON
TALAMINI:Can you bring the microphone
in just a little bit?I'm sorry.

DR.
HOY:I'm sorry.I'm sorry.We have both seen a serious blood loss from a cross‑threading
where the blood connections are made to the dialyzer.I'm not seeing any disconnections from the arms.I'll be happy to show people what our
patients' arms look like.They're a
human factor nightmare.

But
they work.And we have moisture
protectors.We have end uresis
detectors.And we check them.And they work.And we also put an end uresis detector underneath the
machines.And in this particular case,
the patient lost two units of blood.And it wasn't picked up until he woke up and discovered this, and we were
very lucky in that respect.

So
I think that there is an issue here.In
68,000 treatments, we have each seen a cross‑threading or a misthreading
or an over‑exuberant threading of the connections at the dialyzer.You know, how often does that happen in
center?Probably not as often.And maybe that's something we need to
address.

I'm
not seeing inadvertent disconnections at the arms.I don't think we see increased blood loss from treatments.Actually, our hemoglobins on our patients
stay up and are higher than they were when they first come to us.

I
think there may be a potential increased risk of vascular infection due to
button holes.I think we need to
collect the data.I certainly think
there is an increased risk of infections from catheters, despite Dr.
Lockridge's incredible data.

CHAIRPERSON
TALAMINI:I'm sorry?You said you certainly do think so?

DR.
HOY:I certainly do think there is an
increased risk of infection, no more than we see in the in‑center
patients, but I think catheters innately have a higher risk of infection.So I don't think it's an additional risk for
the nocturnal patients, but it certainly is a risk.

And,
finally, I think the psychological effects are ‑‑ I, frankly, am
much more concerned about what happens to my patients in the center than I am
about what happens to my nocturnal patients.I think there is some potential adjustment for care‑givers.

I
think that patients who suddenly have a lot of free time do have an adjustment
to make, but they don't seem to have much of a problem figuring out what to do
with it.

I
am much more concerned about what the isolation and pacification of 300,000 in‑center
patients does as they lose control over their lives and their therapies and
they're too physically ill to socialize, work, exercise, or make love.The emotional well‑being that's
engendered by feeling normal in the nocturnal patients, by their free daytime
hours, by their greater energy, unlimited diets and fluids, and improved
cognition more than compensates most nocturnal patients for the loss of the
companionship of their chronically ill and dying in‑center fellow
inmates.

CHAIRPERSON
TALAMINI:Thank you.Well said.

Dr.
Lockridge?

DR.
LOCKRIDGE:I think it has been well‑said.I think the bottom line is this is a risk
analysis.And there are risks in doing
all of this.And these are outlined
very well.But the benefit is so much
greater for this with the same experience that Chris and I have that this is
about patients doing better, feeling better, living normal lives.

I
think we have to have industry figure out a way to prevent disconnects.I think that is still an important issue,
but it is no greater than what happens in this country.And I don't think it's the risk of putting
people at home to do this any greater than in center.

The
blood loss has been resolved as far as just give them enough iron and enough
EPO and their hemoglobins are higher than they were before with less EPO.

The
psychological issue I think is to think that people ‑‑ there are a
few people that socialize in center, but we are basically doing it to
people.We are making them robots.We're sticking needles in them, and we're
saying, "Come to this time."By empowering people to care for themselves, we are making their lives
become more normal.They're in control
for the first time.

CHAIRPERSON
TALAMINI:Thank you.

So
I'm going to push the panel just a little bit.And, again, these are not any sort of official votes, but the question
it seems to me the FDA wants to know whether they need to be concerned about
the marginal risk of these four things in nocturnal dialysis, as opposed to the
way it's practiced.

So
let me just ask for a show of hands?How many people think for A that there is an increased risk of
inadvertent disconnections, a marginally increased risk for NHD, as opposed to
normal dialysis?Anybody?

(Whereupon,
there was a show of hands.)

CHAIRPERSON
TALAMINI:So we have eight.

DR.
AFIFI:I'm not voting, by the way,
because I'm not an expert in this.

CHAIRPERSON
TALAMINI:Right.And, again, these aren't official
votes.We're just trying to get a
temperature here.

How
about increased blood loss due to the increased frequency of treatments; again,
marginal risk for NHD?Anybody feel
that that's ‑‑ a show of hands?

(Whereupon,
there was a show of hands.)

CHAIRPERSON
TALAMINI:Four.

DR.
ARANOFF:It happens, but does it
matter?That's the issue.

CHAIRPERSON
TALAMINI:Well, the reason I'm not
being more specific is that the FDA wants to know, did they need to be
concerned about this?Is this something
that they need to be additionally concerned about, particularly with the
concept that a document is going to be crafted here?So I'm just trying to help crystallize this for the purpose of
the day.

Comment,
Dr. Moran?

DR.
MORAN:You just rephrased your own
question.Your first question was, was
there a marginal increased risk of blood loss?The answer to that is yes.

And
then you rephrased it by saying, should we be concerned about it?And the answer to that is no.

DR.
ARANOFF:That's correct.That's right.

CHAIRPERSON
TALAMINI:Okay.Fair enough.Fair enough.

How
about the third, potential increased rate of vascular access infection due to
the increased use of access?How many
feel that's a marginally increased risk with home?

DR.
DUFFELL:Well, but should the question
really be again a risk?Is this what we
are worrying about?Should not the
question, though, be restated as before.Is it clinically relevant?

CHAIRPERSON
TALAMINI:Sure.We can phrase it as a clinically significant
risk.

DR.
SADLER:Are we just talking about
infection or are we talking about all manner of vascular access problems
because I think we have all said that we worry about all of them?

CHAIRPERSON
TALAMINI:I'm just trying to keep it to
what it says in C, "potential increased rate of vascular access infection."So no hands?

(Whereupon,
there was a show of a hand.)

CHAIRPERSON
TALAMINI:I've got one taker.

DR.
WEINGER:I think the fact that patients
are doing this and they're doing it way more often has the potential for an
increased risk of access problems.

DR.
LOCKRIDGE:I think that is not a
truism, so to speak.I think they are
better than any person that's in center that's sticking, a nurse or a
technician that is sticking.So I think
it actually goes the other way.

And
I think there is clear literature that has looked at using these accesses.It says that there is no difference.So I don't think it's an issue.

CHAIRPERSON
TALAMINI:And that's probably the
predominant opinion, it appears, of the panel.

MS.
MOORE:May I?

CHAIRPERSON
TALAMINI:Yes, ma'am.Ms. Moore?

MS.
MOORE:I recognize the experts, and I
know that that is the predominant opinion of the panel.But speaking from a consumer's point of
view, even though you may consider the risk minor, I think that it is something
that patients ought to be aware of that it is, you know, a risk.And if something should happen to them, then
they would recognize that they had already been forewarned that this is a risk.

So
I guess I would as the non‑expert on this panel disagree with the
experts.

CHAIRPERSON
TALAMINI:Okay.Thank you.

Dr.
Sadler?

DR.
SADLER:I think that the point that Dr.
Lockridge was making is that they do recognize this is a risk.They do recognize how important their
technique is.And they do recognize it
is their health that hangs in the balance.And that's why they generally do a better job than our staff in the
facility does.

So,
you know, there is a much increased awareness of the importance of every step
they take.And so they generally take
it more carefully, with better habits.And because it's one person doing it every time, I think that there is
not really the increased risk.

And
so, you know, my concern is not so much that the stress gets them down, but the
euphoria of freedom may affect their judgment detrimentally.

CHAIRPERSON
TALAMINI:And I would rush to say that
simply because this panel doesn't think it represents incremental clinical risk
doesn't mean that the FDA is going to forget about it and not bring it up as an
issue with these treatments.But I'm
just trying to force the point and crystallize this particular question.

So
the last one, the psychological effects, how many panel members feel that the
psychological effects of being home, as opposed to the standard treatment,
represents a clinically significant marginal increased risk?Any panel members?

(Whereupon,
there was a show of a hand.)

CHAIRPERSON
TALAMINI:Ms. Moore?So we have one.Do you have a comment?

MS.
MOORE:No comment.Just ‑‑

CHAIRPERSON
TALAMINI:No?Okay.So there were two
other issues that were brought up.And
that is unintended consequences and acute decompensation in the water
quality.Do either of those represent
significantly increased risks for this that panel members want to comment on
further?

(No
response.)

CHAIRPERSON
TALAMINI:No?Dr. Lockridge?

DR.
LOCKRIDGE:Yes.The one thing that was brought up about
antibiotics, I think that because nocturnal dialysis, we do dialysis so much
longer, two and a half times or three times more than what we're doing
now.There are certain clinical issues,
like we dose vancomycin every other day instead of every five days or every
seven days.

So
the actual clearance that does occur, the FDA needs to be aware of this, and
the companies need to be aware of it in their labeling, I think.

CHAIRPERSON
TALAMINI:Okay.Dr. Hoy, comment?

DR.
HOY:I think that the dilemma here is
that we really don't know what we're doing.We know that what we do in center doesn't work very well because we
haven't changed the mortality rates at all.But we really don't know what the net effects of doing a to of extra
dialysis are.

And
we do see some both potential and detrimental side effects or perhaps they are
side effects ‑‑ I don't know ‑‑ of doing a lot more
dialysis, especially with large high flux dialyzers.

For
example, we have now started to see a lowering of beta‑2 microglobulin
levels in our patients, which doesn't occur at first very much but then later
on seems to be coming much more real.

We're
also seeing for the first time, both in center and in the nocturnal patients,
lower B‑12 levels, which we have never seen before.And dialysis patients almost never get low B‑12
levels because it's excreted by the kidneys normally, and they usually have
high B‑12 levels.We're starting
to see elevated MCVs and lower B‑12 levels in these patients because
we're using these huge high flux dialyzers.

So
there's an issue here of the inadvertent consequence, unforeseen consequence,
of this good action, namely using bigger dialyzers.It's probably a risk for both sets of patients, not just
nocturnal.

We
also dialyze off a lot more magnesium.We dialyze off a lot of phosphate.What are the net effects of hypomagnesemia chronically?What are the net effects of hypophosphatemia
chronically we've never seen before in dialysis patients?I mean, we should be lucky to have this
problem.

CHAIRPERSON
TALAMINI:And I would certainly say
that in the absence of a lot of hard data, our job here is to offer opinions,
which you are doing well.

I
would ask the FDA again, being almost out of time for this question, whether
there are other issues with respect to the risk analysis that you would like
the panel specifically to address.And
it would need to be quickly.Any
issues?No.

MS.
BROGDON:No issues.

CHAIRPERSON
TALAMINI:Okay.Thanks.

So
we'll move on, then, to the fourth question, which regards clinical study
design."The FDA proposes that
manufacturers evaluate NHD devices in clinical trials.The purpose of these studies is to evaluate
the incidence of adverse events, the device's ability to deliver prescribed
treatments, and the patients' ability to conduct the treatments as prescribed
in a home nocturnal hemodialysis setting after appropriate training.

"Please
consider the following aspects of the clinical study design and provide input
on the following elements of the study:a) study design; e.g., retrospective or prospective; b) need for a
control group and, if so, appropriate type of control; e.g., prospective,
historical, patient at their own control; c) appropriate sample size; d)
inclusion/exclusion criteria; e.g., exclusion of patients previously on home
dialysis; e) frequency and duration of treatments; f) study duration; g) safety
endpoints; h) effectiveness endpoints; and i) length of follow‑up."

I
would turn and ask Dr. Afifi to begin this discussion as our panel expert on
these matters.Dr. Afifi?

DR.
AFIFI:Thank you.

I
think we should look first at the three items in the second sentence:incidence of adverse events; the device's
ability to deliver prescribed treatments; and, the third one, the patients'
ability to conduct the treatments as prescribed or described.

Item
one let me put aside for a moment.And
I think the other two items, the device's ability to deliver the treatment and
the patient's ability to do it correctly, we can think of those as appropriate
to use a pre/post design; in other words, have patients begin who are currently
in clinic settings and follow them up for a while and measure those quantities
and then do a wash‑out, as the FDA person earlier today described ‑‑
I think it was Dr. Ruiz ‑‑ and then do the same thing for the
nocturnal and then compare the performance, both of the machine and the
patient.So that would be an
appropriate thing.

As
far as adverse events, we need to look at them by whether they're life‑threatening
or not, as I mentioned earlier.If
they're not life‑threatening, then a count of how many adverse events
happen for a given period of time.And
then there are standard statistical methods, plus one or negative binomial and
so on, that gets pretty technical.So I
will leave that alone.But there are
standard ways of doing that.

I
think that would need to be a clinical trial with a control group not having
the patient as her or his own control.In that case, historical controls could be useful if the data are
available in the form that we need them; in other words, how long for a given
period of time.If not, then a
prospective study comparing home to clinic settings with a two‑armed
clinical trial would be the appropriate thing to do.

For
the catastrophic event, life‑threatening, and then the event itself would
either be death or potential death, the appropriate analysis is what we call
survival analysis.In that case, we
don't count how many times the patient died obviously.We measure, rather, how long until that
catastrophic event has occurred.

And
then the relationship of that to whether this is a home patient or a clinic
patient and a bunch of other co‑variates to be adjusted for would be the
job of the analysis.

So
this will take me more than a minute and a half.Is that okay, Dr. Talamini?

CHAIRPERSON
TALAMINI:Yes, yes, sir.

DR.
AFIFI:Thank you.

So
this is as far as the study design on the options and the potential control
groups.Sample size computations would
depend on the particular outcome.So
there is really no recipe as such.

Each
study would need to be handled differently perhaps.Inclusion and exclusion criteria, I would obviously rely on the
clinical people in such studies.

The
frequency and duration of treatment, it seems already the FDA has proposed a
standard.And I think the experts in
this area need to review that, whether five to seven days a week.And I think this is what is meant by this
point unless it is something else.

Study
duration and the length of follow‑up are closely related.In general, we in designing a clinical
trial, especially one that will look at length of time until a catastrophic
event occurs, we look at the half‑life, if you will, what is the median
survival, the median disease‑free or survival time, because we want to
come close to actually observing half of the patients have the event occur to
them.Otherwise there would be too much
censoring in the terminology of such studies, so some review of the literature
to look at how long does it take until ultimately the patient dies and how long
does it for half of the patients to experience that.So that would be my advice on the length of follow‑up.

Effectiveness
endpoints is something I think that is best discussed first by the clinicians
but, then, also with input from other experts, such as statisticians,
epidemiologists.And, as I mentioned
earlier, I'm glad to see the FDA thinking of using epidemiologists more.They can't contribute more than just the
clinicians or the statisticians can.

So
these are my comments.And there are
more technical things that I don't think we need to go into now.

CHAIRPERSON
TALAMINI:Thank you very much.That's very helpful.

We'll
just start from there and go around.Additional comments on any of those points and perhaps particularly the
effectiveness endpoints?Dr. Sadler?

DR.
SADLER:Since this is a clinical trial
to evaluate a device, when the question of retrospective versus prospective
comes up, your immediate assumption is, well, it should be done
prospectively.But if somebody comes
with an existing device that has been used a great deal in this arena, I would
imagine retrospective data if it is good and complete and accurate would be
very useful.

I
don't think we can have an ABA switch with these people because in the first
place, if you get people in the dialysis center and they get habituated, they
don't want to change anything.

And
if you get somebody dialyzing at home, he doesn't want to come back into the
center.So you take one or the
other.You put them there.And so you may take historical controls or
some sort of additional control group that would be carefully matched.

I'll
leave the size of the group to the statisticians.And I would think that this could be both people on daily and
people on less frequent nocturnal dialysis.

It
certainly doesn't need to go on for an extended period of time to demonstrate
that the device is effective, that it doesn't induce user errors, so I would
think something like six months, which would get you close to 100 treatments on
alternate days and over 100 treatments on every day.And certainly once that had been established, the time would
probably shorten for subsequent devices.

The
safety endpoints certainly should be user errors, should be machine failures,
should be false alarms and real alarms, and interruptions of therapy due to device‑related
or user mishaps.And those would also
be much of our endpoints, plus demonstrating that the patient's meter exceeds
the DOCI guidelines.

CHAIRPERSON
TALAMINI:Terrific.Thank you, Dr. Sadler.

Dr.
Schulman?

DR.
SCHULMAN:I'll just make two
comments.One thing is that the
endpoint, one of the endpoints, should be the delivery of adequate
therapy.And I would recommend using a
GOCHA standard, Kt/V method of kinetics be considered in such a study.That I think is an important way to quantify
this.Even though this isn't a survival
study, it would show efficacy of the actual treatment.

And
the other comment is that because this study isn't going to ‑‑ you
cannot do a really randomized trial in a study such as this.So there is likely to be bias in the way the
patients are selected.And you are
going to have to rely on your statistician to employ the necessary techniques
to account for that bias.

CHAIRPERSON
TALAMINI:Thank you.Perhaps you could expand on why you couldn't
do a randomized trial.

DR.
SCHULMAN:Well, I mean, you really
couldn't take ‑‑ a lot of this, the experience of Lindsay is that
when he tried to recruit patients for the study, it was really patient‑motivated,
the ones that would want to actually come out of the unit and go into the home
and do this.

And
so you really couldn't pick a truly equally randomized group.You had social issues and different level
motivation in the patients that went into the home, these nocturnal therapies.

CHAIRPERSON
TALAMINI:It seems to me with the right
funding mechanism, you might be able to convince patients, but I don't know.

DR.
WEINGER:Can I follow up on that?I have heard this from several people, and I
am not understanding it.Since this is
only going to be for certain patients anyway, if the entry criteria is those
patients who are interested and then you promise everybody "Ultimately
you'll get it, but we're going to randomize half of you as the control group to
stay in clinic and the other half get it" and then use an intent‑to‑treat
approach, I don't understand why that wouldn't be a reasonable design.

CHAIRPERSON
TALAMINI:Dr. Hoy has a comment.

DR.
HOY:Can I respond to that?You know, the NIH and CMS are actually
trying to do this.The problem is that
there has never been a successful dialysis study that has randomized people to
two different dialysis modalities.

In
other words, we have never compared CCPD, continuous cycle peritoneal dialysis,
to CAPD.We have never compared home
hemo to in‑center hemodialysis.We have never compared transplant to hemodialysis.And we are now proposing to talk about doing
a randomized controlled trial of in‑center hemodialysis against short
daily hemo in‑center dialysis and nocturnal home hemodialysis.

You
know, I've got to tell you I'm participating in this because I think it is the
gold standard.And I think, actually,
if CMS and NIH can get together, probably you ought to think about trying to
get information from them as well.But
there has never been a successful study that has collected patients for two
different modalities.

CHAIRPERSON
TALAMINI:But if it could be done, it
would be a worthy goal, I would assume.

DR.
SCHULMAN:You could do things like
develop propensity scores for the patients and do certain techniques like that,
but that's the way you get around.I
don't think you'll get a truly randomized trial.

CHAIRPERSON
TALAMINI:Okay.Well, Dr. Lockridge?Then I need to get us back on track.

DR.
LOCKRIDGE:Right.I think we really are focusing on the wrong
thing here in the sense of a clinical trial that is going to prove
efficacy.I think that in the initial
definition, we were talking about a trial that looked at a device that
delivered the same capability as another device that already existed and
whether it was safe.

And
that doesn't include whether the endpoint is death or not.It includes whether or not the machine is
safe and delivers the same form of therapy.

So
I think we are way out here to think about a six‑month trial or a two‑year
trial randomized.I think we are really
looking at a much different trial.

CHAIRPERSON
TALAMINI:Thanks.

Let
me go back to going around the room, even though we have sort of gotten ahead
of ourselves a little bit.Dr. Duffell?

DR.
DUFFELL:I don't know if my comment is
going to pick up where you left off or not, but my thought behind this is the
presumption that a clinical trial is indeed needed in order for a manufacturer
to put one of these products on the market.

Is
that a true assumption?Will the data
bring forth a knowledge base that will enlighten us in some way that it is
going to really help in the marketability of these products?Because from the conversations I have had
with you all around the table, it seems like everybody wants these things.They want them pretty much now.

So,
you know, the question you need to ask yourself is, is what we're going to get
out of this trial really going to enhance our knowledge and change what we are
doing because it is going to delay the availability of the technologies to you
all as clinicians.

So
is there a return on this investment, in other words, from a business
standpoint, not whether the questions are valid, because the questions maybe
could be addressed somewhere else, some other method, such as post‑market
surveillance registries and things of that sort, where you gather information
and revise labeling based on what you learn that way?So do you need it prospectively now in order to put these things
out there or can we get it some other way?

DR.
SADLER:Very quickly.We already have them.And it may very well be that the
manufacturers will not ask.And they
can't be refused if they don't ask.And
so none of this will come to pass.

If
somebody wants to get it, they will have to go through the hoops, whatever
those hoops happen to be.And, as I
said, if it's a machine that has already been out there and has a significant
track record, they can probably do it with retrospective data if it's complete
and accurate.

CHAIRPERSON
TALAMINI:Ms. Moore?Pass.

Dr.
Hoy, further comments?

DR.
HOY:Just one.I think there's a huge amount of data from
Canada.And I know it's a foreign
country, but it might be worth thinking about trying to see whether or not the
retrospective data that we have in the United States combined with the data
from Canada actually gives us some ideas about the safety of this method.I mean, there is a lot of data out there.

CHAIRPERSON
TALAMINI:Dr. Lockridge, further
comments?

DR.
LOCKRIDGE:Yes.I'm still missing the point here.I think it's not about the safety of the
modality as much as the safety of the machine.The safety of the machine and the modality related to nocturnal
dialysis, the patient asleep night over night.

There
are over 500 articles written about more frequent dialysis.Seven years ago, people didn't believe it
was better.It's no question that the
nephrology community believes that more frequent and longer dialysis is
better.The real question is, can a
manufacturer make a machine that can safely deliver nocturnal dialysis if they
apply for that?

So
I think we need to answer that question for the FDA.What kind of study does that do?I think it's a prospective.I
mean, similar to what Aksys did with their study, it's eight weeks in center,
training period, eight weeks at home, see how many alarms there are, how many
times the machine is down, is it safe, does it disconnect.I mean, it's a pretty simple thing.

To
randomize to approve mortality in the NIH study, they're saying we have to do
1,500 people and follow them for 2 years.No business people are going to do that to deliver a machine to the
community.We have got to really be
realistic here about what we're asking for.

CHAIRPERSON
TALAMINI:Yes.Those are good comments.

Dr.
Moran?

DR.
MORAN:Next time I'm going to sit
upstream from Dr. Lockridge.I do have
to agree with him.I think the study
design should be what was done by both machines that have undergone trials for
home use, a period of training in center, and then a period being followed in
center, and then a wash‑out at home, and then collection of safety data
in the home.So each patient is their
own control.

I
entirely agree we will never get a randomized study if we try and do that.I think the only way to design the study is
to have each patient in each arm.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Blagg?

DR.
BLAGG:I agree with both Dr. Moran and
Dr. Lockridge, and I also take up John's point that, after all, we have all of
these machines out there now that were never designed to do home dialysis, but
they're working perfectly well with home dialysis.

So
if a manufacturer wants to get specific approval for home dialysis, I think the
sort of approach that John Moran is talking about and Bob is a way to do
this:brief, simple.

And
the only question I think is, should you use patients who are already home
patients to do the study on or should you use patients who are in the center
but who are willing to go home?

I
think that may be very difficult to achieve in terms of patient numbers in a
reasonable amount of time.So I think
that the minimum study is what we should be looking at.

DR.
GILLESPIE:And just on a slightly
different note, in terms of inclusion and exclusion criteria, I would hope that
the age range will be very broad and that the criteria will be very broad.That would help improve the numbers of the
study as well, but it's actually young people that have perhaps some of the
most to benefit from this modality and might actually be a larger proportion
overall using it because of the benefits on nutrition and growth and on reduced
school absenteeism.

So
there is certainly no reason to exclude people under 18 or anything like that
from these kinds of studies.

CHAIRPERSON
TALAMINI:Thank you.

Let
me just take the prerogative of the chair for a second.So if I hear the majority and what they're
seeing, it's that the more frequent dialysis is no longer an unanswered
question.That's a question that has
been answered in the literature.

And,
like usual, the key to doing the right study is asking the right question.And the question here is simply, are the
machines safe enough to do it at home?Is that what I'm hearing people say?

DR.
ARANOFF:I think you also have to
consider, will the specific machine provide the treatment also?I mean, the modality is proven, but we're
talking about individual machines at some time.So the machines are going to have to demonstrate that whatever
that machine is also provides a treatment.

CHAIRPERSON
TALAMINI:Right.Dr. Schulman?

DR.
SCHULMAN:I don't disagree with the
suggestion of Dr. Moran about how this study should be done and what the
purpose of the study is, but I don't want the FDA to go away thinking that it's
a slam dunk that longer dialysis is better.

The
whole nephrology community thought that a higher Kt/V was better.And in a real trial, the null hypothesis was
fulfilled.So let's not go into that
part of things.

I
think I just want to make that cautionary note.

CHAIRPERSON
TALAMINI:Okay.It looks like we're going backwards now, but
let me get Dr. Kalota, and we'll get back over.

DR.
KALOTA:Well, I just see it as two
separate issues.One, whether daily
hemodialysis is better, longer hemodialysis is better, is a medical issue.It's not a device issue.And I thought we were here for the device,
which is whether it's safe or not, whether it's comparable or not, not whether
to decide whether we should be dialyzing more often, longer, slower, or faster.

CHAIRPERSON
TALAMINI:Okay.Dr. Gibson, do you have a comment?

DR.
GIBSON:I just support the idea of the
minimal studies about the device.That's all.

CHAIRPERSON
TALAMINI:Dr. Weinger?

DR.
WEINGER:Yes.I think we have to separate safety from efficacy.And if you simply are testing the device, it
might make sense to have for efficacy a trial of this new home‑specific
device and an older not home‑specific device used in the home.That would test whether it was as good as
existing.

But
safety is a different thing.And I want
to reiterate the importance of useability testing before you try and do
efficacy testing.That, then, gets at
the issue of inclusion and exclusion criteria.The temptation whenever you are doing a clinical trial is to have as
narrow a group of patients, the best possible patients so that you can show the
best possible result.

But
if you are trying to look at safety in such a clinical trial, you're going to
get a best case scenario of safety.And
so you have to pair that with separate useability tests with a broad spectrum
of potential users and use environments so that you really understand what the
constraints are in terms of safety of the modality.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Moran, further comment?

DR.
MORAN:I think that is entirely the
wrong attitude.What you are suggesting
is that we should test these machines in patients who the doctors don't think
are safe to go home.People entered
into this study need to be the people who are potential users of the machine,
not the worst‑case scenario.

DR.
WEINGER:But you misunderstand me.In a useability test, what you want to know
is what are the potential failure modes, errors, and such that patients can
make?And if you pick the best possible
patients and you do a limited clinical trial, you are going to pick up some of
those things, but you won't pick up a sufficient number that will reduce the risk
of in post‑market seeing catastrophic events.

And
that is why useability testing, where you are looking at worst‑case
scenarios, what if there is a disconnect, what if there is this and that in
simulated environments, mind you.

Then
you can tell, did my design or warnings or whatever you do really ‑‑
is it going to work at preventing a catastrophic outcome.

CHAIRPERSON
TALAMINI:Well, I don't feel as good
about where we came to at the end of that question's discussion because of the
complexities involved, but it sounds at least like the panel's opinion is that
the prime objective of the study needs to be to test the safety of the machine.

It
sounds like there is a difference of opinion as to whether these should be
naive patients or experienced patients.And is that worth discussing a little bit more for such a study or not?Dr. Sadler?

DR.
SADLER:Well, one of the key
characteristics of a good machine for home is that it's easy to learn.So certainly part of the testing ought to be
while the patients are training.And
you can't train somebody who is already trained.So I would think yes, it ought to be incident patients, rather
than prevalent patients.

Again,
I think because most of the existing machines are already in use for this
purpose and no specific labeling for this purpose has ever existed, I think it
is highly unlikely that there is a motivation for the manufacturers to come
forward and seek it.And we're probably
just having an intellectual exercise here.

CHAIRPERSON
TALAMINI:Dr. Afifi, summary comments?

DR.
AFIFI:Yes.I think the concept of substantially equivalent that the FDA uses
says that, indeed, what we want to do is find the comparison machine, the
currently used one in clinics and the new proposed one.And, therefore, having the patients be their
own controls, start there, wash‑out period, then do it at home and
compare the results.I think that that
is an appropriate way of thinking to my mind.

The
question of long‑term effectiveness and long‑term safety could I
think be thought of as a post‑marketing concept.And that is the best that I could offer you.

CHAIRPERSON
TALAMINI:Terrific.Let me go on to question 5, which is more ‑‑
yes?

MS.
BROGDON:I believe the staff had one
question they wanted to ask.

CHAIRPERSON
TALAMINI:Okay.Please do.

MS.
BROGDON:It was just answered.Thank you.

CHAIRPERSON
TALAMINI:Oh, okay.Terrific.So question five is with regard to clinical study design, "Please
address these additional issues and discuss whether or not they should be
considered in a clinical trial:a) need
for dialysate additives, such as phosphate, and monitoring requirements for
these levels; b) type of anticoagulant appropriate for home use; e.g., dose,
bolus, and monitoring issues; c) type of hemodialyzer membrane and
permeability; d) type of monitoring; no partner present, partner awake, no
partner but using remote monitoring, or no partner or remote monitoring; e)
vascular access choice and location, and risks associated with these; f)
practice of hemodialyzer reuse; and g) psychological effects; e.g., impact of
treatments on patients, such as loss of social interaction and the effects of
the increased responsibility on the patient, and the impact on and the reaction
of the family members living in the house).

I
guess what I might suggest that we do as we go around the room is if you don't
feel these need to be studied in the context of what we have already discussed,
state that.If so, then state perhaps
why it should be part of such a study.

Let
me start with Dr. Sadler and go around so that Dr. Afifi can summarize after
this question.

DR.
SADLER:Okay.In this particular question, I think that A, B, C, and E are
clinical practice and not part of a device investigation.My own feeling with regard to D is that I
would be very reluctant to send anybody home without a partner.I just think that to do so is to believe
that Murphy was wrong.And I believe
that things do go wrong, and that is when the partner is needed.

With
regard to F, for most patients dialyzing at home, reuse is more trouble than it
is worth.And there are effective
single use dialyzers these days that they could utilize.

And
with regard to G, that's not really a factor in the device so much as it is
clinical practice again.There are both
beneficial and stressful effects on patients at home.And without observation of the individual patient, it would be
inappropriate to generalize those.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Schulman?

DR.
SCHULMAN: With respect to these
dialysis additives, I think it's known that the phosphorous levels, for
instance, may go down.And they're
going to have to be supplemented.That
is something the patient is going to have to do.

And
the device, it should be, that behavior should be, tracked how easy it is for
them to do, how often, does it affect the curve, because the phosphorous level
went to low and so forth.So I think
that that is part of monitoring that should be done in a study design.

So
I do disagree with Dr. Sadler.With
respect to most of the other things he said, I'm in agreement.

CHAIRPERSON
TALAMINI:Okay.Dr. Duffell?

DR.
DUFFELL:I agree with Dr. Sadler's
remarks.

CHAIRPERSON
TALAMINI:Thanks.

Ms.
Moore?

MS.
MOORE:No additional remarks.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Hoy?

DR.
HOY:I agree with Dr. Sadler's remarks
about A, B, C, and E being clinical decisions that the physicians have to deal
with.The monitoring issue, to me the
patient has to be monitored in some way, shape, or form, whether it's by a
partner at home or by a virtual partner.It doesn't matter to me because I think they're both equally safe or
equally risky depending on how you look at it.

The
practice of dialyzer reuse is unnecessary and inefficient.Ask the largest dialysis company in the
world about that one.They don't do it
anymore.It would just interfere with
the ease of being at home.

I
do think the issue of the impact of this treatment on other family members
needs to be looked at, care‑givers, other care‑givers, spouses,
significant others, and children.It is
worth investigating further.

CHAIRPERSON
TALAMINI:So, Dr. Hoy, let me just pin
you down and perhaps Dr. Sadler a little bit more on this.This issue of monitoring and partners, is
this an issue worthy of study or no in a trial that the FDA would participate
in?

DR.
HOY:No.

DR.
SADLER:I think not.It's been demonstrated that both work.There is preference on the part of
individual nephrologists who will train patients.And they will practice in conformity with their beliefs, but the
evidence is already out there that people can do it both ways.It's just a matter of how much of a margin
of safety exists.And I don't think
that it's appropriate for this study.

CHAIRPERSON
TALAMINI:Thank you.

DR.
HOY:I'm sorry.One last comment I forgot to make about the
issue of not reusing dialysis.There is
the issue of first use reactions.And
we have not run into trouble with that because we recirculate blood for 10 to
15 minutes before we actually hook the patient up.But that is an issue to be looked at if you're not reusing
dialyzers.

CHAIRPERSON
TALAMINI:Dr. Gibson wants to make a
comment quickly.

DR.
GIBSON:Yes, very brief, about the
psychological effects.I agree with the
industry representative, Dr. Duffell, that it should not be incumbent on the
industry to prove that this is psychologically safe.

But
if I understand Drs. Sadler and Hoy to say that we should not collect data on
the psychological effects on the family during the study, I think that would be
wrong because, even though it's my opinion, like theirs, that there will not be
any psychological effects that are harmful during this period, I think we
should collect the data.And there are
some fairly simple instruments that at least have a validity among the
behavioral health people with regard to outcomes versus the process of coping,
which is a different story.

But
as far as outcomes are concerned, that data could be collected.My hypothesis is that it will not show any
adverse effect, but I don't know that.

CHAIRPERSON
TALAMINI:Yes.I was actually pinning them down on the
monitoring issue.I think Dr. Hoy
actually was in favor of studying the psychological aspects.

DR.
SADLER:Well, if I may comment, I
didn't say at all we shouldn't study it.I just said that I thought it was not something to be generalized on
small populations because people will respond in different ways.It certainly should receive attention
because it is always important when we put this kind of a responsibility on a
patient.

CHAIRPERSON
TALAMINI:Dr. Lockridge?

DR.
LOCKRIDGE:Yes.I probably disagree a little bit about what
should be done as far as the dialysate additives.I think nocturnal dialysis is different than daily dialysis,
short daily, or in center 3 times a week in the sense that it offers 2 to 3
times more dialysis or clearance, clearance of about 30 to 40 cc.

So
in our practical experience, I think that phosphorous is a real issue.And I think new machine designs to the field
should address that and figure out how to make the phosphorous at 1.5 to
2.In other words, that should be part
of the machine design.

The
issue of magnesium that Chris brought up, everybody is hypomagnesemic, I think
that needs to be looked at in this document that says what you should do to
bring this to fruition as far as the manufacturer.Magnesium is an issue.

And
the third issue is calcium.I think
they have clearly shown that when you dialyze this amount of dialysis is
actually calcium wasting, there are no phosphate binders or no calcium
supplement that patients take.

So,
actually, with hemo filtration or removal of the fluids, you're removing
calcium.And people become calcium‑depleted.So I think that we standardly start people
on three milliequivalents per liter of calcium.The standard bath in center is 2.5.

So
I think calcium is another thing that really has to be looked at.You really don't see the changes on the
bones for a year, but I think we need to have the manufacturers be able to
deliver a 3, a 3.25, and a 3.5 calcium bath.And it needs to be proved that they can do that in this trial because
that is going to be needed to care for these people.

DR.
SADLER:Bob, isn't that incumbent on
the concentrate manufacturers, not the machine manufacturers?

DR.
LOCKRIDGE:Well, it depends on what
machine and who is ‑‑ I agree if you're Fresenius and using the
standard proportion machine.If you're
Aksys and make your own concentrate or if your renal solutions that are using
absorbent cartridge or next stage, you mix the fluid in a bag.They have to bring that to the marketplace.

CHAIRPERSON
TALAMINI:Dr. Moran, which of these
items should or should not be included in a study?

DR.
MORAN:Reuse should not be
included.I don't think anybody is
doing reuse in the home patients.I
apologize.I agree with Dr.
Sadler.It's more complicated than it's
worth.I apologize.I'm upstream of you.

Water‑soluble
vitamins is the other thing I think we should be looking at, too, in this long‑extended
dialysis.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Blagg?

DR.
BLAGG:I basically agree with Dr.
Sadler's comments.The other comment I
would like to make, though, is we really need to look or somebody needs to look
at what this trial is going to cost the manufacturers to do the more of these
things that get put into it because I think that will be one of the reasons why
manufacturers may never want to go and have their machines approved for nocturnal
hemodialysis.

CHAIRPERSON
TALAMINI:And that is one of the
beauties of being on an FDA panel, that we're not supposed to think about cost.

Dr.
Gillespie?

DR.
GILLESPIE:Just to comment on the reuse
thing, I think it doesn't make sense in the traditional sense with traditional
machines, but it's possible that people are going to come up with different
technology.

I
know there is one machine right now that reuses not only the dialyzer but the
entire circuit.And it's self‑cleaned
each night.So I think we couldn't
write off the reuse question entirely if somebody comes up with a novel
technology for it.

I
wouldn't see people like collecting the dialyzers and carrying them back into
the center to reprocess, as was done in the past.Like I said, if the machine is something that is categorically
different, then we may have to look at it differently.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Lockridge, did you want to make a comment?

DR.
LOCKRIDGE:Yes.The heparin issue is a real issue, too,
because because you dialyze people six or seven or eight hours, the design, you
can bolus, but the kidney is going to clot.When my patients forget to cut on the pump, their kidney clots during
the night.

So
I think it's FDA should be having the manufacturers have a machine that has a
heparin pump on it that will deal with that anticoagulation.And how that heparin pump works and how it
is monitored needs to be monitored in this clinical trial.And that makes this different from
nocturnal.I mean, nocturnal is
different in that way.

CHAIRPERSON
TALAMINI:Yes.Right.That's helpful.

Dr.
Weinger, which issue should be ‑‑

DR.
WEINGER:I'll pass.

CHAIRPERSON
TALAMINI:You'll pass?

Dr.
Gibson, further comments on which of these should be included in a study and
which not?

DR.
GIBSON:Pass.

CHAIRPERSON
TALAMINI:Pass?

Dr.
Kalota?

DR.
KALOTA:I can't comment on the things
specific to the hemodialysis, but I would say for the test, we should have some
kind of monitoring present to answer the question as to whether or not we need
to have monitoring present.

CHAIRPERSON
TALAMINI:Okay.

Great.Dr. Aranoff?

DR.
ARANOFF:I think it's less important
for us to consider which ones of these individually specifically should be
studied and more incumbent upon us to comment about whichever ones are studied
for a particular device, that that then be covered in the labeling of that
device.

So,
for example, we may have technology where a particular machine would use a
dialyzer that has heparin covalently bound to the membrane.And so it wouldn't need bolus or infusion
heparin to keep it one.That ought to
be covered, then, in the labeling for the device as it is studied.

If
a device is studied with both remote monitoring and a partner, if that
manufacturer chooses to use their machine and study it in that way, then that
ought to be included in the labeling, that this was shown to be safe with a
remote monitoring and the partner.

If,
on the other hand, a device manufacturer chooses to study their device without
remote monitoring or without a partner and still proves it to be safe, then
they ought to have that indication.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Afifi, summary thoughts about these issues and the clinical study question in
general?

DR.
AFIFI:Yes.First, it seems that none of the items A through G under this
area need to be thought of as randomization variables.In other words, we don't need to randomize
do you have a monitor or not, do you have an in‑resident person or not,
et cetera?

I
think it would be wise to collect the data on them.I don't think that will be a burden, an excessive burden.I think the point that if we then collect
those variables and look at them as covariates and perhaps do some
stratification or subgroup analysis, we will learn about whether some of these
items, some choices for these items, are more helpful than others for the
success of the whole operation.

And,
as Dr. Aranoff said, I think these could be helpful conclusions to be included
in the labeling later on.

CHAIRPERSON
TALAMINI:Terrific.Thank you.

I
would again ask the FDA if there are further issues the panel can address to
help with this clinical study design question.

MS.
BROGDON:I need to confer with the
staff for just a moment if you would allow that.

CHAIRPERSON
TALAMINI:Sure.There was a housekeeping detail that
somebody mentioned about the front desk and needing to ‑‑ okay.

DR.
SADLER:Well, while we have a gap, let
me put one loose comment into it.

CHAIRPERSON
TALAMINI:Absolutely.

DR.
SADLER:It's been a thought that has
been rattling around since we started that we talk about training laymen to do
dialysis at home and dialysis in center being done by professionals.But those professionals are ordinarily
technicians who have a highly varied and relatively short period of
training.The difference is not so much
the quality of the people doing the dialysis but the presence of oversight.

CHAIRPERSON
TALAMINI:Good point.

Yes?

DR.
RUIZ‑ZACHAREK:Yes.We actually wanted to elaborate on the
psychological effects.One of the
concerns we had ‑‑ again, this might just fall in the practice of
medicine and individual prescription by each nephrologist.

Our
concern was, how stable would a patient need to be to go home with a dialysis
machine to perform nocturnal dialysis.And our concern was on patients who have prior suicidal attempts or some
psychological instability.

CHAIRPERSON
TALAMINI:So let me ask perhaps if four
of the clinical nephrologists could address that for us.What four clinical nephrologists would like
to address that question?Dr. Lockridge
obviously would.

DR.
LOCKRIDGE:I think there are criteria
for who should not go home.We treat
nocturnal dialysis as a privilege in our facility.And we look at it similar to a transplant.

In
a transplant, basically if you're a drug user, you have to be drug‑free
for six months with randomized studies.So that's dealing with the drug user.

If
you're an alcoholic, you have to be alcohol‑free and be tested.And if you smell of alcohol, it's looked
within the document, in six months, you don't get a chance to dialyze, to do
nocturnal dialysis.And if you have mental
health issues, you should not be allowed to go home.

We
have found that education is not an issue.We have taken cards.We have
sent people home with third grade or less education to do it.It is the desire to do it.If the patient wants to do it, they can do
it.

So
I think that teaching, taking the same approach that this is a privilege and
treatment it as if it's a transplant patient and having the same requirements
for drugs, mental illness, and alcohol is the thing.

As
far as the issue of stability, we feel that having the social worker makes a
social work visit in the home by herself with the family to try to get a feel
for the family interaction, which we think makes a difference as far as what
kind of input.

We
have trained people that weeks into training the wife said, "the machine
or me in the bedroom."And
certainly the person took the wife in the bedroom, instead of the machine.

So
I think there are limitations of what we can do, but I think that is where I
would structure it.

CHAIRPERSON
TALAMINI:Dr. Gibson?

DR.
GIBSON:I would like to start by saying
what I said before, that I would not like to see arbitrary exclusions based on
the psychological data because, frankly, psychiatrists are not all that good at
predicting who is going to do what in the future.And nobody is all that good at predicting human behavior with any
certainty.

With
that said, I think Dr. Lockridge is right on target that the evaluation needs
to be center‑specific, much like transplant programs, where transplant
programs do exclude people who are actively using substances and people with
unstable mental illnesses.And that is
certainly appropriate to do, but I would certainly argue that there are very
likely people with stable mental illnesses who do extremely well on home
hemodialysis of any modality.So that's
really all I would like to do, is just make a plea for not excluding people
based on what you think is going to happen.

And
there is one other point.I mean, the
active substance abuse and unstable mental illness I would view as exclusions
from entering the program, but when people are in the program, of course,
they're going to be trained.And during
that period of training, you have an opportunity to evaluate how people are
actually doing.

And
my prediction is that, of course, like everything else, we'll be surprised that
some people you will predict will just pick this up in a flash and do well,
will flunk, and never go home and people that you will predict are just dumb as
dirt will learn how to do this procedure just fine and will stay at home and never
come back.

CHAIRPERSON
TALAMINI:Which leads nicely to the
next question.Any other burning
comments in response to that?Great.We've got a process comment.We're doing great, but we've got to pick it
up just a little bit.So on to question
number 6 with regard to training.

The
training of patients and their partners, if applicable, is crucial in
performing NHD treatments.Please
comment on the training needs for this modality in terms of the important
aspects to be included in the training program, how long the training period
should be, and what criteria should be used to determine if a patient has been
adequately trained and is ready to begin self‑care at home.Please also consider who should do the
training and how they should be qualified.

Dr.
Blagg, let's start with you.

DR.
BLAGG:Okay.First of all, training needs obviously have to cover various
things.The first thing, in our program
at least, is to teach the patient to stick themselves or if family members can
do it, to teach them because our experience is it is difficult for patients to
learn until they feel at least reasonably comfortable with sticking themselves.

They
need to know about their disease.They
need to know about dietary management and so on.They need to know how to do the dialysis.They need to know the complications that are
likely to occur and how to handle them, how to contact for support and when to
see their physician and so on.

How
long a training period?In our program,
once the patient can stick where we take three to four weeks to train the
patient, we train them three days a week.And the other two days, they come in and go to classes and do other
things, like work on the equipment and so on.

Criteria
to be adequately trained.We have a series
of tests of various procedures that the patients do that the nurses do with the
patients on a regular basis.They have
a final exam, if you like, on which they have to reach a certain minimum score
before they're allowed to go home.

During
the last couple of so dialyses that they do in the training program, they're in
the room with the door shut, and they're talking to the staff by the telephone,
like you would at home.

Staff.I think the important thing ‑‑ I
don't think it really matters whether it's a nurse or in some cases a
technician.I think what you need is
somebody who has a lot of experience of dialysis and who is capable of being a
teacher, not just a treater, and keep their hands off patients if they make
mistakes, let patients learn from their mistakes.And I think that covers ‑‑ how they should be
qualified, well, I guess each individual unit is going to decide how to qualify
their staff.

Those
are my comments.

CHAIRPERSON
TALAMINI:I guess I would ask the panel
also to think about how much of this falls into medical practice and how much
of this should really be ‑‑ I don't want to use the word
"legislated" but should be part of whatever is done in terms of the
FDA.As Dr. Weinger pointed out, there
are now procedures where training is absolutely essential before you can
perform the procedure.So think about
that as well in your comments.

DR.
BLAGG:I would suggest that it's the
physician in the dialysis unit's responsibility to take care of these things.

DR.
WEINGER:Yes.I think that the issue of where is the boundary between the
manufacturer's responsibility for their specific device and the clinical
environment is a very important one.

The
manufacturer certainly to assure success in the use of their device and, thus,
the sale of more of them is going to provide general guidance for the clinical
aspects of it, but, really, the focus has to be on the device.And my advice there is that the manufacturer
needs to establish clear performance criteria for the key elements and
components of their device and perhaps then provide suggestions and some
support materials perhaps for helping the clinician attain those performance
criteria, helping the clinicians to train the patients to attain those
performance criteria.

But,
really, it's about the patient needs.This would be typically what one would call a useability objective.Patients needs to be able to tend to and
respond appropriately to X alarm in Y amount of time correctly.Those are the kinds of performance criteria
that a manufacturer needs to identify.

And
hopefully they will have in parallel with developing the device developed
training materials and tested these things themselves so that they know that
those are effective materials to attain those performance criteria.

CHAIRPERSON
TALAMINI:Dr. Gibson?

DR.
GIBSON:I like the idea of the
performance objectives and agree with everything Dr. Blagg said and nothing
else to add.

CHAIRPERSON
TALAMINI:Dr. Kalota?

DR.
KALOTA:Nothing else to add.

CHAIRPERSON
TALAMINI:Dr. Aranoff?

DR.
ARANOFF:I think Dr. Blagg described
home training very well.And I don't
think that nocturnal home hemodialysis with regards to training is
fundamentally different than routine home hemodialysis with regards to the
training characteristics.

And
I think that could even be applied to the psychological issues that we
discussed a moment ago.A patient who
is appropriate for home hemodialysis or home therapy, whether it's home hemo or
PD, should be a candidate for nocturnal as well.

So
I don't think this is fundamentally different than the guidance the FDA has
already given for training.

CHAIRPERSON
TALAMINI:Terrific.I haven't heard much about who should do the
training other than the physician.So
perhaps as we go around, we could address that as well.Dr. Afifi?

DR.
AFIFI:No comment.

CHAIRPERSON
TALAMINI:Dr. Sadler?

DR.
SADLER:I agree with Dr. Blagg that the
training should be done by somebody who is interested, a good communicator, a
teacher, and well‑experienced in dialysis.And it doesn't matter what credentials they hold.They can be very effective.

I
do believe that this represents a function of the dialysis facility.It's the practice of medicine.And while it was perfectly reasonable to ask
the facility to certify that the patient has been trained, has demonstrated capability,
and been tested on this, you shouldn't get into that box to see what's in it.

To
quote Mark Twain, "No generalization is worth a damn, including this
one.And we ought to be entitled to
have a little bit of variation."

CHAIRPERSON
TALAMINI:Dr. Schulman?

DR.
SCHULMAN:Well, I agree with what has
been said already.I would like the FDA
to know that the people who do home training, whether it's CAPP or hemodialysis
as it exists now, often among the motivated personnel.And they generally tend to do a good job and
are given the latitude by most units to spend as much time as they need with
the patient.

So
I don't think that should be a major concern of the FDA.

CHAIRPERSON
TALAMINI:Okay.Terrific.

Dr.
Duffell?

DR.
DUFFELL:I agree with Dr. Sadler.

CHAIRPERSON
TALAMINI:Ms. Moore?

MS.
MOORE:Yes.I agree with Dr. Blagg and the others who spoke about the
training for home care, but I think that the manufacturer should take some kind
of responsibility for guidelines for training the medical staff, who will then
be responsible for training the persons who are going to be doing this at home.

CHAIRPERSON
TALAMINI:Okay.Great.

Dr.
Hoy?

DR.
HOY:I don't think that the
manufacturers do very much to help us train our technicians.There may be some very broad stuff they give
us, training materials, but basically we train our technicians to do
dialysis.And those technicians are
actually no different in education or background usually than many of the
patients who come to us.

Several
comments about the training process that we use, one, we find that we can't
train the first week.We dialyze them
four times a week for the weeks that we do the dialysis.And we do it very aggressively because by
the end of the first week, they're less anxious.

We're
sort of describing what we're doing.We've also gotten to know them a little better.We've decided which one of our three
trainers is going to be a personality fit with those patients.And we've got them cognitively improved by
the end of the week so they remember what we're saying.

Secondly,
we also do everything we can to chart self‑care in the dialysis unit in
center before they come to us.And we
start cannulation training before they come to us.

CHAIRPERSON
TALAMINI:Great.Thank you, Dr. Hoy.

MS.
MOORE:Excuse me.

CHAIRPERSON
TALAMINI:Yes, Ms. Moore?

MS.
MOORE:I think I mentioned the
responsibility of the manufacturer because I remember being on a prior panel
where there were machines and the manufacturer had some very clear training
packages for the physicians because each machine then I think is designed in a
special way, maybe very simple training, but it seems to me that a physician
might need some kind of guidelines when there is something new introduced in
his office, such as a new machine.

CHAIRPERSON
TALAMINI:Thank you.

I
think probably what we're caught up in a little bit again is the difference
between nocturnal home dialysis and standard in‑hospital dialysis, where
the practices are already pretty well‑established with regard to
physicians and others using the machine.But that is an excellent comment.

DR.
WEINGER:Can I follow up on that just
briefly?Based on other devices that
have been put in the home and certainly drugs that are being used at home, the
manufacturer would probably have substantial ‑‑ it's a two‑way
sword but probably have substantial liability if they left all of the training
of the patient to the clinician.

So
any manufacturer who didn't have a comprehensive patient training program would
be in trouble.So you can anticipate
they're going to have that.And,
therefore, we want to make sure that it's effective.

DR.
DUFFELL:One other comment.All manufacturers have an FDA responsibility
to them to provide adequate instructions for use.That's just an absolute given.So they have to be there.

CHAIRPERSON
TALAMINI:Right.

DR.
SADLER:But one quick comment.Now, we get surveyed all the time by several
different agencies that come and tell us that we have to follow the
manufacturer's recommendation.I'm
sorry, but I was doing home dialysis training before these people started
manufacturing machines.And I really
don't want them telling me how to train people for home dialysis.

CHAIRPERSON
TALAMINI:So noted.

(Laughter.)

CHAIRPERSON
TALAMINI:Dr. Lockridge?

DR.
LOCKRIDGE:Well, Dr. Sadler, I may have
to disagree with you here, but there are less than 1,000 people doing home
dialysis in this country right now.There are 300,000 people doing it.We are rigging new devices to the community that have new ways of doing
things.The Aksys machine is totally
different.The renal solution is the
next stage.

I
think it's FDA's responsibility to clearly have the manufacturers produce
training manuals that are very detailed and complete.The CMS as far as who can train or who cannot train, it's clearly
stated that an R.N. has to oversee, that L.P.N.'s can train but an R.N. has to
oversee a home training program.That's
the standard of care.

Now,
you can certainly use technicians.You
can use L.P.N.'s.Two of the ladies
that train in my unit are L.P.N.'s.They're very good, but they're overseen by an R.N.CMS has already covered that.

But
I think that either we are going to get to in this country with just 1,000
people centers that are specialized in home training, like Wellbound, or we're
going to have to have standardization of care if we're going to make a dent in
this care.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Moran?

DR.
MORAN:I agree with what has been
said.We have full independent home
training centers.And our first
criterion when we hire a new nurse is, are they going to be good trainers.Experience with a particular machine comes
second to that.We have all three of
the new machines in our centers.And we
expect the nurses to be able to teach any patient on any of those machines is a
strict policy.I think that is
something else we have to do.

We
don't want to get into the old system, where we had PD nurses and hemo nurses
and never the twain shall meet.We want
the nurse to be able to train a patient on PD in the morning and the Aksys
machine or the Next Stage machine or the Fresenius machine in the afternoon in
a different patient.

CHAIRPERSON
TALAMINI:Okay.Dr. Blagg, further comment quickly?

DR.
BLAGG:I would like to disagree with
you.I think if you have enough
patients, you have a separate program for PD and home hemodialysis.

I
also think that the physician who cares for the patient probably will have very
little to do with the trainings, maybe the medical director of the facility,
but we have 45 physicians in Seattle.And most of them don't know anything about training.We just hope they will refer their patients
to be trained.

And
a final comment that we haven't mentioned is that we believe that, at least
every year and preferably every six months, one of the training nurses should
go out and see the patient do a dialysis in the home to make sure they haven't
acquired too many bad habits.

CHAIRPERSON
TALAMINI:Excellent point.

Other
questions regarding training?Let me
just ask specifically the FDA whether they would like the panel to address
other issues regarding training.

MS.
BROGDON:I think we have enough
information.Thank you.

CHAIRPERSON
TALAMINI:Terrific.Thanks.

So
the last two questions the panel is asked to address are with regard to
labeling.Question number 7, device
labeling directed towards the patient should include information on NHD and on
the device, including instructions for the use and care of the device, how to
deal with alarms and how to run treatments.Please discuss other important aspects of NHD and the value of including
them in the lay user's manual; e.g., treatment, not device risks, psychological
effects of the treatments, vascular access, information.

Dr.
Gillespie, would you be willing to start the round?

DR.
GILLESPIE:That's kind of a tough
question to answer right off the top of my head.

CHAIRPERSON
TALAMINI:We can pass if you'd
like.No problem.

DR.
GILLESPIE:Okay.Appreciate that.

CHAIRPERSON
TALAMINI:Dr. Weinger?

DR.
WEINGER:First, labeling, just so
everybody is on the same page, is not just a physical manual for use.It includes all aspects, written and
electronic, related to the use of the device, including, to some extent,
warning and instructions physically attached to or displayed by the device.

And
so the bottom line with regard to the patient, which is the focus of this
question, is again that one needs to test that whatever the piece of
information is, that it effectively transmits that information to the patient
in the condition and situation where that information needs to be used.

And,
as well, I want to make sure and appreciate that there are lots of modalities
and for lay people, often instruction manuals in the traditional sense are the
least effective way of transmitting that information.

Again,
the drug companies I think have a fair history now of various programs from
videotapes and DVDs and Web sites and telephone hotlines, et cetera, that need
to be considered in the design of these kinds of instructions, labels, and
such.

DR.
GIBSON:I don't see any value of
putting anything on the label about possible psychological effects.

CHAIRPERSON
TALAMINI:Thank you.

DR.
KALOTA:Pass.

CHAIRPERSON
TALAMINI:Dr. Aranoff?

DR.
ARANOFF:I think in 25 years, I've only
had one patient, one home patient, ever quote anything out of an instruction
manual to me.

(Laughter.)

DR.
ARANOFF:The patients ignore them.They learn from the training what to
do.And they don't read the instruction
manuals.

However,
with the ability now to have instructions embedded into the useability of the
machinery, that is where our attention should be focused.

And
the instructions should be simple.They
should be sequential so that patients are not given information that they don't
need at the very moment that they are doing something.That is, if they are setting up the machine,
the instructions should lead them through it, "Push the green button.Now push the red button.Now push the yellow one.Now you're ready to start."

And
then once they start their treatment, so on and so forth, and then when they
finish their treatment, then come off the machine and clean it out or whatever,
that should be sequential.And
fundamentally the machine should diagnose what is going on and tell them what
to do about it.

CHAIRPERSON
TALAMINI:So that is an excellent
point.With that point in mind, let me
just ask the FDA or any panel member who knows to what degree embedded software
that is actually part of the patient interface can be considered labeling or is
it never to be considered labeling?

MS.
BROGDON:We would consider it labeling,
but that's the extent of my knowledge on this.I can confer with the staff if you want to give me a couple of moments.

CHAIRPERSON
TALAMINI:No.I only ask it for the benefit of this discussion because
certainly as these machines become more sophisticated, indeed much more of the
information that is needed is in the software and not a piece of paper.

MS.
BROGDON:It is certainly a developing
area for FDA.

DR.
WEINGER:It is part of the user
interface and, therefore, subjected to all of the good manufacturing practices
and other design controls.

CHAIRPERSON
TALAMINI:Let's keep going around the
room.Dr. Afifi?

DR.
AFIFI:I was just looking at the list
of things here.I didn't see water
purification.I'm wondering if that
could be added to it.

CHAIRPERSON
TALAMINI:Dr. Sadler?

DR.
SADLER:I would like to reinforce what
Dr. Aranoff said about having the machine's software lead you through
this.I think that question seven is
inevitably tied to question eight.And
the question eight is going to produce a manual for professionals.And then you turn that over to some experts,
who translate it down to a fifth grade reading level.And that will satisfy the requirements.

But,
as he says, it's not very important to patients because they may keep it as a
reference to look something up sometime.And so it ought to be laid out so that you can find things in it.

The
most important part of the training is the materials that are provided by the
person who does the training and by how the machine gives them feedback as they
operate it.So that I believe that
doing it as a software function is much more desirable.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Schulman?

DR.
SCHULMAN:I have nothing further to
add.

CHAIRPERSON
TALAMINI:Dr. Duffell?

DR.
DUFFELL:I agree with Dr. Aranoff, but
I would also add that our professional staff doesn't read manuals either.

(Laughter.)

DR.
DUFFELL:I mean, I think we fool
ourselves.It makes us sleep better at
night to have things covered there, but the realization needs to be back to the
design of the product to make it intuitively obvious.

CHAIRPERSON
TALAMINI:As soon as the manual becomes
complicated, the first thing you do is make a phone call anyway, rather than
thumb through the manual.

Ms.
Moore?

MS.
MOORE:Pass.

CHAIRPERSON TALAMINI:Dr. Hoy?

DR.
HOY:I have nothing to add.

CHAIRPERSON
TALAMINI:Dr. Lockridge?

DR.
LOCKRIDGE:Yes.I think FDA needs to think about this
entirely differently.I think that we
need to tie the labeling and the training manual and what is embedded in the
machine altogether as one thing.

I
think that we have rewritten our training manual six times now over the last
seven years.We have little cards that
we use now.And when we call the
patient, they do refer to the manual if it's used in a training manual.So to have a label like what the FDA
requires on a drug is worthless for the patient.The patient doesn't use it.

But
if you have a labeling that ties in the training, the machine, and the
embedding of the ideas in there, that is very useable to the patient.And I think that is what we should be moving
toward.

So
I would favor the combining of labeling, training manual, and software in the
machine.

CHAIRPERSON
TALAMINI:Excellent point.

Dr.
Moran?

DR.
MORAN:I think our experience says that
having a graphical user interface and a touch screen are absolutely wonderful
for training, establishing confidence in the patient.And in a situation where an alarm occurs, if the machine tells
them, as Dr. Aranoff said, what the problem is and what the steps to follow
should be, one, two, three, and they don't even have to think, I would point
out that if they are in bed at night and they are awakened by an alarm and
you've got a graphical unit user interface that automatically lights up ‑‑
I beg your pardon.I was saying if they
are in bed at night, if they are awakened by an alarm, if you have a graphical
user interface that automatically lights up, and they're not fumbling for the
light switch and everything like that, they can just reach out and do the
appropriate ‑‑

CHAIRPERSON
TALAMINI:Great.Thank you.

Yes?

MS.
BROGDON:I just wanted to say to Dr.
Lockridge we support the evolution of user and patient labeling.We do review all of that information.And we try not just to require paper
labeling just because FDA has always gotten that.We're open to more innovative types of labeling and also then
training.

CHAIRPERSON
TALAMINI:Dr. Blagg?

DR.
BLAGG:I agree very strongly with Dr.
Moran about the touch screen, and I have nothing else to add.I agree with particularly Dr. Aranoff.

CHAIRPERSON
TALAMINI:Great.

Dr.
Gillespie, further comments?

DR.
GILLESPIE:I agree with what people
have said, that the importance of printed manuals is dwindling in a world where
more interactive types of things are becoming commonplace.

I
think also part of the problem with printed manuals is that a lot of them are
really not readable and not very useable, even by professionals.And that's why people don't use them.So certainly we support any progress in
making things that are more user‑friendly.

The
question also asks about other aspects of nocturnal hemo and whether those
should be included in the user manual like just general treatment risks and
psychological effects and vascular access.And I don't think so.

I
think the manual should stick to just the machine and try to keep it
concise.And those other areas, like
things about access are a separate issue that people should discuss with their
health care professionals or with other materials made for that purpose.

CHAIRPERSON
TALAMINI:Okay.Summary comments about the patient labeling
because in a moment we're going to discuss physician labeling?Dr. Weinger?

DR.
WEINGER:Yes.I just want to follow up.Some of my colleagues provided a reasonably effective design solution to
a specific user need with regard to specifying a touch screen and such.I think we need to step back from that
because especially the FDA's job isn't to design devices for manufacturers but,
rather, to see if manufacturers designed devices effectively for use.

And
so the important thing is for the manufacturers to have an effective human
factors engineering process where up front they identify what are the key
issues with regard to labeling and instructions and the ability of the patients
to respond to alarms, for example, and then to establish performance criteria
and then, whatever their design solutions are, to demonstrate those solutions
meet the performance criteria.

One
can be misled.I'll give you an
example.AEDs we all know.And the human factors folks put them forward
as examples of here are devices that were designed with human factors
engineering involved so that eight‑year‑olds can do defibrillation
of strangers in airports.

But
we have some data that shows that the voice, which is a very powerful guide to
getting the end user of that device to do what needs to be done, is, in fact,
too powerful sometimes.And we have
videotapes of providers who are shocking people over and over and never getting
around to pushing on the chest and actually getting some circulation going.

So,
again, you have to really evaluate your solutions with the end goals in mind.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Lockridge, did you have a comment?

DR.
LOCKRIDGE:Yes.I think that I have a mixed feeling about
this.We talked about how much
information should be in the manual, the patient's manual, about NHD and how
much should not be.And I feel strongly
that the physician and the patient should be making that decision.

And
I think that that is what you were saying, Dr. Gillespie, that this is a
clinical decision.But I think we need ‑‑
you know, how much do we do?How do we
do that?And I don't totally know how
to do that at this time.So I'm mixed.

CHAIRPERSON
TALAMINI:Okay.Questions from the FDA for the panel with
regard to patient labeling?

MS.
BROGDON:Dr. Mendelson had a comment he
would like to make on human factors.

CHAIRPERSON
TALAMINI:Okay.

DR.
MENDELSON:My comments will be
concerning labeling and human factors in general, what our activities are at
FDA.I guess I want to reinforce what
Dr. Weinger said.

I
talked about a process when I did my talk.And I want to emphasize that we try not to be burdensome and
prescriptive.We never tell a
manufacturer what shape knob to use, what type of sound a user should
hear.What we like to do is look at the
manufacturer's process.So if they're
labeling, if their design works according to their human factors evaluations,
that is satisfactory to us.We don't
tell them what to do.

CHAIRPERSON
TALAMINI:Great.Thank you.Appreciate that.

Okay.Final question, number eight, with regard to
physician labeling, the physician labeling, prescribing information, typically
includes the indications for use, contraindications, warnings and precautions,
instructions for use, and clinical data on the use of the device.

For
NHD, there is other important information that clinicians need to know, such as
the need for alarms that may not be part of the NHD device; e.g., circuit
disconnect alarms, fluid leak or moisture detection alarms, the need for a
partner or for remote monitoring, vascular access requirements, and the need
for dialysate additives; for example, phosphorus.Please discuss whether or not this and other treatment
information should be part of the physician labeling.A lot of these are issues we have already discussed, but this is
with respect specifically for the physician labeling.

Dr.
Weinger, would you like to begin?

DR.
WEINGER:Sure.I have two points I wanted to make.One is that one of the things it seems to me
ought to be part of this is guidance to the clinician on patient selection and
evaluation.My colleagues on this side of
the table have vast experience, but that needs to be transmitted efficiently to
those who are trying to do this for the first time.

The
second thing that I haven't heard about and I think needs to be in this area is
a proper way of evaluating the home environment, which includes a variety of
issues that have been mentioned in our early presentation beyond water quality,
which I heard about, but lighting, noise, distractions, clutter, other
stressors, and issues of when and who and how that home environment evaluation
would occur.

And
then, finally, I just want to put on the record because I didn't hear it
mentioned and I think it may be important in terms of the design of the device
for the patient to respond to a crisis situation, and that is fatigue and
circadian effects.And I heard somebody
early on having sleep people involved in the conversations, but that may
actually be a real design issue.

CHAIRPERSON
TALAMINI:Great.Thank you.

Dr.
Gibson?

DR.
GIBSON:Actually, I find this question difficult
and don't quite know how to respond to all of this.So I think I'll pass for that.

CHAIRPERSON
TALAMINI:All right, sir.

Dr.
Aranoff?

DR.
ARANOFF:Well, I'm not sure exactly how
much comes under physician labeling and would fit into a technical manual, for
example, of the issues that would be very device‑specific.For example, the home environment was
mentioned.

Different
devices will require different water pressure.For example, whether that goes in the physician labeling, or whether
that is a technical specification in an owner's manual of some sort, I don't
know but that sort of information.

I
think in this, the one comment I would like to make about physician labeling is
that it ought to reflect how the device was proven to be safe and
effective.That is, it should describe
the situation in which it has been safe and effective.And I made that comment about monitoring and
so forth earlier.

CHAIRPERSON
TALAMINI:Dr. Afifi?

DR.
AFIFI:Nothing to add.

CHAIRPERSON
TALAMINI:Dr. Sadler?

DR.
SADLER:With regard to the additional
points made in this question, my answer is no.

CHAIRPERSON
TALAMINI:Thank you.That's clear.

Dr.
Schulman?

DR.
SCHULMAN:I think some of the issues
that are listed here, for instance, of phosphorus down in this case, don't
necessarily have to be part of the labeling for the physicians.Just some of these functions should take
place as a CME type of a thing, you know, where we learn the procedures from
experienced people, like Drs. Lockridge, Hoy, and Blagg.But I think these things don't have to be
labeled for the physician.

CHAIRPERSON
TALAMINI:Okay.

DR.
DUFFELL:I agree with Dr. Aranoff.

MS.
MOORE:I pass.

CHAIRPERSON
TALAMINI:Dr. Hoy, what should be in
the physician labeling?

DR.
HOY:I have to tell you I have never
read a physician label on a machine or a dialyzer, for that matter.

Secondly,
anything that you would put in there that has to do with the actual practice of
nocturnal dialysis will probably be out of date by the time it's bought off the
shelf.So I think it's not worth
anything more than just doing what you would normally do for the device.

CHAIRPERSON
TALAMINI:Okay.The fact that it goes out of there quickly
might not mean it shouldn't be done in a manner that could be updated in a
timely fashion.So I wouldn't
necessarily ‑‑ you know, the one doesn't preclude the other is what
I suggest.It could be on a Web site or
something.

Dr.
Lockridge?

DR.
LOCKRIDGE:I have mixed emotions about
this.I still go back to 1,000 people
in this country doing some type of home hemodialysis.I go back to the fact that there are only two training centers in
this country that train people to do nocturnal dialysis.And I think there are some differences.Three.Excuse me.There are some
differences in nocturnal dialysis as far as the calcium, the phosphorus, and stuff.

Maybe
it's not in physician labeling, but I think the companies need to be
responsible.If they're getting
approval for a nocturnal machine, I think that somebody has got to be
responsible to know that the people who are using those machines understand the
differences.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Moran?

DR.
MORAN:I have a mixed response.Looking at the list there of the examples, I
think physicians do need to know that they do need to know some sort of full
legal motion detection if that's not part of the machine.I think they do need to know the need for a
partner for remote monitoring.The
vascular access requirements I don't think are necessary.

And
I think the need for dialysate additives, as has been suggested, there are a
lot of people who don't know a lot about nocturnal hemodialysis.

CHAIRPERSON
TALAMINI:Okay.Thank you.

Dr.
Blagg?

DR.
BLAGG:I agree.Nothing else to add.

DR.
GILLESPIE:And I agree with what has
previously been said, too.I think you
have to base the label on whether it has been proven to be safe.And if that involved adding a third party
item to the setup, then you have to let people know that you are doing that.

With
regard to ‑‑ what was the other thing?I'm sorry.That's all I
have to say.

CHAIRPERSON
TALAMINI:So it sounds like the
predominant view on the panel is that these details should not be part of the
physician labeling.Is that what I'm
hearing?Dr. Lockridge, you had a
comment?

DR.
LOCKRIDGE:I was going to comment about
the sleeping issue that was brought up.Actually, there are studies now that show that the rotational sleep
pattern that occurs in normal people will go away with in‑center
hemodialysis three times a week.And it
actually comes back to normal terms with nocturnal.So the sleep disorders actually improve.So it's an enhancement or help for people to
respond appropriately when they deal with it at night.

DR.
WEINGER:Though if they're like me, if
they get paged at 3:00 in the morning, their response is not going to be as
sharp as if they're awake in the middle of the day.That was the point I was making.They may be normal, but that's still an issue because it's happening in
the middle of the night.

CHAIRPERSON
TALAMINI:Any further issues regarding
labeling that the FDA would like the panel to address?It has to be fairly brief.

DR.
MITCHELL:This is Dr. Dianne Mitchell.

I
just want to clarify.I think what I
heard was a comment to the effect that it would be, somehow or another, helpful
to make a statement about that the physicians need to have an appropriate
understanding of what nocturnal home hemodialysis is in comparison to
conventional hemodialysis because the concerns are a little bit different
between the two.And that is actually
something that we can on some level put in the labeling.

Now,
my interpretation of the conversation was that that would be a reasonable thing
to do, but I didn't hear that directly.

CHAIRPERSON
TALAMINI:Thank you.

So
let's put that quickly to the panel, whether physician labeling for a device
for NHD should contain information on the differences between standard dialysis
and NHD.Is that ‑‑
no?Help me.I want to make it as clear as I can.

DR.
MITCHELL:No.We can't say, "You must be a board‑certified
nephrologist in order to use this machine," but we can say things like
"You must have experience or training in nocturnal hemodialysis in order
to prescribe this."

CHAIRPERSON
TALAMINI:Okay.So should physician labeling contain that sort
of a statement?Dr. Lockridge, what is
your opinion?

DR.
LOCKRIDGE:No.I think FDA is going too far the other way
now.I would not have them say that
unless you had some type of training because what is determined is
training.Is it going to a CME class
about this?

I
think that the responsibility is to let the physician known in some manner, the
manufacturer know where it's different.And the difference is related to the base.The difference is related to the monitoring and those issues.

So
there is a difference that needs to be spelled out somewhere.I'm not sure it needs to be in the labeling,
but it needs to get across to the physician.But to say that you can't have somebody on home dialysis because ‑‑
I just don't think we want to get into that.

CHAIRPERSON
TALAMINI:Is there a panel member who
thinks physician labeling should contain such a statement?

DR.
SCHULMAN:I think that a general
statement like when we use cyclosporin or agents like that, that the person
prescribing should have some experience with immunosuppressant agents, I mean,
that said and not more than that.

CHAIRPERSON
TALAMINI:Other opinions from the panel
regarding whether some sort of a statement ‑‑ now, obviously, we're
not going to wordcraft the statement, but should labeling address this
issue?Dr. Weinger?

DR.
WEINGER:I mean, I suspect that there
is some kind of statement like that on a regular hemodialysis labeling.We're really talking about how is this
different from conventional.And I have
to agree fully with Dr. Lockridge that outlining what are some of the
differences or at least providing references to documents that outline those
differences would be reasonable.

CHAIRPERSON
TALAMINI:Okay.Terrific.

That
is great work on the panel's part.I
would like you to be thinking about the summary statement.After our public comment, I want to get each
panel member to make a brief summary statement.

OPEN PUBLIC
HEARING

CHAIRPERSON
TALAMINI:But we do need to go to the
open public hearing portion.Now that
the panel has responded to the FDA questions, we will proceed with the second
open public hearing of this meeting.

Prior
to the meeting, we received one request from Rod Kenley of Aksys, Limited to
speak during the afternoon open public hearing.And I need to read the disclosure statement before having that
comment.Is Mr. Kenley here?Yes.Okay.Great.

So
let me read this statement, "Both the Food and Drug Administration and the
public believe in a transparent process for information gathering and decision‑making.To ensure such transparency at the open
public hearing session of the advisory committee meeting, FDA believes that it
is important to understand the context of an individual's presentation.

"For
this reason, FDA encourages you, the open public hearing speaker, at the
beginning of your written or oral statement to advise the committee of any
financial relationship that you may have with any company or group that may be
affected by the topic of this meeting.

"For
example, this financial information may include a company's or group's payment
of your travel, lodging, or other expenses in connection with your attendance
at this meeting.

"Likewise,
FDA encourages you at the beginning of your statement to advise the committee
if you do not have any such financial relationships.If you choose not to address this issue of financial
relationships at the beginning of your statement, it will not preclude you from
speaking."

So
with that having been said, I will invite Mr. Kenley to make his public
comment.

MR.
KENLEY:Thank you.

Yes.My name is Rod Kenley.My credentials are that I have been on the
manufacturing side of the business now for about 28 years, about half that time
with Baxter and the second half with Aksys Limited, the company that I founded
back in 1991, with the specific intent to manufacture and design a machine for
daily hemodialysis, daily home hemodialysis.

I
would like to first start off with advising both the panel and the participants
from the FDA to think about the broad picture effects on the industry in
general and innovation, in particular.

When
I started Aksys Limited, that was the first occasion in the business of kidney
dialysis that there was a start‑up company funded by private money.It wasn't a corporation that was preexisting
in other areas that got into the dialysis business.

When
I was out trying to raise the capital to start this company, I met with a lot
of potential investors.And I got one
question from every single one of them.Will this require a clinical trial?What will be the length of the FDA review process?Because they always translate that back to a
return on their investment.

My
answer was always the same.There has
never been a clinical trial required in the history of mankind for a
hemodialysis machine.Unfortunately, I
was proved wrong.We became the first
machine that was required to do a clinical trial.

We
figured it cost us about $70 million.It kept us off the market for an additional two years, in addition to
the cost of the actual clinical trial.

If
you require clinical trials for each small step forward in a modality change,
you've got to think about the effects on what we're all supposed to be here
trying to do, treat these patients better, because it's only through these
kinds of innovations that these patients get treated better.

Dr.
Lockridge made a comment that before 1996, almost nobody was talking about
daily dialysis.And when we did start
talking about it in '95 and '96 at the annual meetings, there was universal
skepticism except for a few early adopters, like the doctors who are present
here.

Now
it's basically universally accepted that that is a better form of therapy.So we've got to ask ourselves, is what we're
doing creating a higher risk of keeping patients off a more beneficial therapy
than it is in reducing risks that if they go on that therapy, they're going to
be injured?

Now,
to that point in specific, I would like to talk about hemodialysis machines
that have been around now for four years.They are some of the safest medical devices that you can possibly
imagine.

We
do 45 million treatments in this country alone every year with an
extraordinarily low incidence of patient injuries related to the machine.Every hemodialysis machine that is on this
market fails safely.Absolutely it
fails safely.There is almost no way a
patient can interact with a machine that will cause injury to themselves.

I
can challenge people to describe how that can happen.We can debate that.But
next I would like to take on some of the specific issues that have been talked
about here in this afternoon's session.

With
regard to requiring a clinical trial to prove the safety ‑‑ and I
think we establish that efficacy is not at issue here.If you use a dialysis machine to treat a
patient that has no kidney function, it's efficacious.The question is, is it safe when it's
used?So any clinical trial would
really be looking at whether a particular device according to its indications
for use is safe.

Blood
access, the first item here is additional safeguards to prevent blood access
disconnections, completely unrelated to a hemodialysis machine.

There
is no way that my machine nor any other ever built or designed can detect a
venous needle disconnection.If it
could have been done, it would have been done a long time ago because you could
sell a lot more machines.The simple
fact of the matter is you cannot detect the change in venous pressure if the
needle comes out of the access site.

You
have a window of venous pressure in which the machine is allowed to operate in
order to prevent these nuisance alarms.By the way, there's no such thing as a false alarm.If there's an alarm, it's because it hit a
preset limit of some kind.There are
nuisance alarms.

If
you set those pressure alarm limits too tightly, you'll get them going off all
the time.You've got to operate within
this range of pressure.And it's within
that same range that you could get any kind of a change in the venous pressure.

If
you expect the dialysis machine manufacturer to develop a device that
identifies that blood is now dripping off the patient's arm, like these
enuresis pads, I think you'll be waiting a long time.Consider the product liability issues there.Those things are not 100 percent
effective.What if a patient bleeds out
and we manufactured that device and it didn't alarm soon enough or at all?

Also,
it's not really related to the practice of hemodialysis.When you build a hemodialysis device, you
build a device that sends blood through an artificial kidney and dialysate
through an artificial kidney and assures that it's done safely.The pressures are safe.The temperatures are safe.The conductivity is safe.There is no air going to the patient.There is no blood coming out of the
dialyzer.

That's
all we can do for you.To ask us to
assure that the venous needle stays in the patient arm is not part of our
deal.I wish it were.If it could be done, I would have done it
before.

Software
incorporated in the device, allowing connection to the internet, nice to
have.It might help me sell more
devices.It's not a minimum requirement
to treat a patient safely on nightly dialysis, same with central monitoring, as
we have heard, I think, multiple occasions.

User‑friendly
design.Who will design a study that
quantitatively determines that your machine is now safe because its user‑friendliness
is above a certain hurdle or it's not safe because it's below a certain user‑friendly
hurdle?As I said before, there's
almost no way a patient can interact with one of these machines and hurt
themselves, fortunately.

The
quality of water.To the degree that
that is integrated with a machine ‑‑ and it's rarely
integrated.It happens to be in our
machine.I think the issue is valid in
terms of how much extra water they see.

I
agree with most of what was said around here.The current standards are adequate.What you should be more concerned with is the quality of the dialysate.That is, after the water is mixed with the
dialysate concentrates and what is the inflammatory stimulating quality of that
solution?

Yes,
Dr. Sadler, there's not conclusive proof, a whole lot of suggestive
indications, that the lower the inflammation stimulation on these patients, the
longer they'll live without amyloidosis, the longer they'll live without
atherosclerosis and malnutrition.

As
far as a clinical study design, we have to, as was said here, prove that we are
substantially equivalent to another device.Let's take my example.I have
now made a device that has gone through a clinical study and has been on the
market for two years with essentially no patient adverse events that is cleared
with an indication for daily home hemodialysis.It's used any number of hours.

Most
people have told us that our graphic user interface represents the gold
standard in terms of communicating with the patient clearly and directly, as
you have all suggested you would like to see with a big flat panel display and
a touch screen.

That
is all well and good, but when it comes to now going through a clinical study
to prove that my same device is used safely for nocturnal use, what more do I
need to prove?Currently my device can
be used for one hour, two hours, three hours, four hours, five hours, six,
seven, or eight hours.In fact, it is
already.

What
is it about a hemodialysis machine that is less safe in the fifth, sixth,
seventh, or eighth hour than it is in the second, third, or fourth hour?The answer is nothing.It cannot get less safe.It already is as safe as it can possibly be.

And
with regard to the dialysate prescription, that has to be individualized
according to the device.Our device
happens to use a batch.All 50 liters
of dialysate that you're ever going to get are there at the beginning.That means ‑‑

CHAIRPERSON
TALAMINI:Excuse me.I'm sorry.About one more minute.One more
minute.So I just want you to have an
opportunity to summarize.

MR.
KENLEY:Thanks.That means that the phosphate removal will
not be as large as if you used a single‑pass device.So, in fact, what we found in our nocturnal
treatments is that the phosphate removal is almost optimal.So there may not be a need for phosphate.And that is a different device.

The
dialysate are regulated under their own 510(k)'s as their own devices.And those are stand‑alone from the
machines for the most part.

Psychological
effects are clearly not related to the machine.Increased rate of vascular effect infection, not related to the
machine.Increased blood loss, not
related to the machine.

Training,
who is going to design the experiment that says what is the cutoff for good
training material for us to train the clinicians versus inadequate training
material?It's completely subjective.And I have run into many occasions where
physicians have told me, "Don't tell me how to train patients.I know."Clearly they do know.What we have got to do is send our clinical nurse educators in there to
train their trainers on how our machine is used, not how to do dialysis.

So,
in summary, I appreciate the opportunity to address the panel.And I hope you would consider the
suppressing effects that any form of regulation can have on the expansion of
new technology and innovation in any industry but particularly in this one.

Thank
you very much.

CHAIRPERSON
TALAMINI:Thank you, Mr. Kenley.Is there anyone else here who would like to
address the panel now?Please raise
your hand if so.

(No
response.)

CHAIRPERSON
TALAMINI:It looks like we have nobody
else who wants to make comments.Since
there are no other requests to speak in the open public hearing, I'd now like
to ask for final comments from the panel and from the FDA.

So
if each panel member could give a minute or two summary on today's proceedings
and the issues that we have discussed, we would be deeply appreciative.Dr. Hoy, perhaps you would be willing to
begin.

7.FINAL COMMENTS

DR.
HOY:I'm actually going to be much more
specific.Oddly enough, we haven't talked
about the machine issues.And my staff
and my patients were very clear that I was to bring up four issues that they
were concerned about that have to do with these machines.

One
is the transducer protectors tend to leak.They're designed for four‑hour treatments.They tend to leak.You have to put a second transducer protector on to get through
the night.So please design them so
they fit more tightly and don't leak.

Secondly,
the machines are a little noisy, especially mixing water.They'd like them less noisy.They'd also like the ROs less noisy.

Thirdly,
pH and conductivity need to be able to be checked independently by external
meters preferably.We're also concerned
about redundancy because in the Fresenius 2008H, there is only one conductivity
meter.In our code machines in our
dialysis center, there are four in‑series conductivity machines.So it's much more fail‑safe.We'd like more redundancy.

And,
finally, our patients are tired of mixing bicarbonate in containers.They would like to develop machines that use
the bicart, cartridges that are designed to last for eight hours.

I
have nothing more to say.Thank you.

CHAIRPERSON
TALAMINI:Again, the privilege of the
chair.If I could just ask for the
opinion, particularly of those of you with the most experience in this.If you were to look down the road five
years, what you might see in terms of numbers of patients with this sort of a
therapy.

DR.
HOY:I think there are two questions
there.One is how many patients can do
it.I believe that about 20 percent of
our patients in our unit could do that.

Now,
I think the issue of how many are going to be doing it five years from now
really depends on how realistic physicians get on how to run a business because
physicians think that if you're not being reimbursed at a profitable rate for
one unit, then it's not worth doing it.In fact, you have to make a bunch of widgets before you actually start
to make profits.And although we're a
not‑for‑profit, our operating margin is real.So I think there are issues there about the
way that physicians look at how one does this.

This
modality is perfect for the insane health care system we work in, which is so
labor‑intensive and capital‑intensive because our staff costs are
half or less of what they are in center.And the supply costs are the one area of price elasticity that is
available in the future.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Lockridge?

DR.
LOCKRIDGE:First of all, I would like
to thank the FDA to have me here to make comments.

Second
of all, I do think that more frequent daily nocturnal dialysis is the
future.If you had a disease that the
incident year that you had that disease, 23 percent of people would die and
thereafter every year 17 percent would die and that, in fact, is still
increasing and has not improved over the last 15 years and that we were
spending 8 percent of the monies that were spent on Medicare for less than .5
percent of the patients, I feel that we as nephrologists, we as the FDA, we as
the government have a responsibility to reach out and to seek new ways of doing
things.

This
is here.It's acceptable.It is a better way.We need more, better technology.Training people how to use machines that are
in‑center machines is not acceptable.

I
think the FDA needs to be wise in trying to figure out how to approve quality
of one machine versus the other and safety, but we need to get on with trying
to have new technology come to the market.

If
we had new technology come to the market, I'm planning on ‑‑ about
11 or 12 percent of my population now are doing nocturnal dialysis.My goal is to have 25 percent in 2 to 3
years.If I have new technology, I feel
that I can easily reach that.

Can
you imagine being 35 or 40 years of age, have a high school or less education,
working a factory, where you're making reasonably good money and have hope you
get end stage renal disease and your disability check is $600 and you are
trapped to come to an in‑center unit 3 times a week to feel lousy?That is going on across this country on a
routine basis, 300,000 people.We have
got to make a difference in what our people are seeing and spend their money
wisely.It is my money.

Thank
you.

CHAIRPERSON
TALAMINI:Thank you, Dr.
Lockridge.It's well‑said.

Dr.
Moran?

DR.
MORAN:I agree with a number of at
least 20 percent of people should be going home.Whether they will be going home in five years is another issue.

I
constantly hear people say that in this country to so many people that couldn't
go home.And that's absurd to say
that.There are so many people who
couldn't have a transplant, but that doesn't mean we shouldn't be doing the
maximum number of transplants we could do.The more people we get home, the better for the system and especially
for the patients and the taxpayer.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Blagg?

DR.
BLAGG:Again, thank you for asking me
to come.Just a couple of brief
comments.One comment that I think has
some bearing on everything we have talked about today is a comment that Dr.
Scribner made in about 1965, which was basically that with any chronic disease,
the more the patient knows about the disease and its treatment and the more
responsibility he's able to take for that, the better rehabilitated he will be
at every sense of the word.And I think
that is what we are trying to do.

I
would hope that as a result of what we have said and done today, that the FDA
in its wisdom, whatever it decides to do bears in mind that we have to change
the numbers of patients.

Bob
may get to 25 percent.I agree.I think 20 percent of more of patients could
do it with the right equipment and everything else.The problem is, though, besides providing the right equipment,
we've got to make the large dialysis corporations much more enthusiastic
towards this system.

We've
got to educate physicians, most of whom have never seen home dialysis.They just think it's a strange thing that
goes on in Lynchburg or in Seattle or somewhere.And we have to educate patients that this is one of the best
things for them.And I just hope that
whatever the FDA comes up with will not serve as any sort of deterrent to
increasing the numbers of patients.

Thank
you very much.

CHAIRPERSON
TALAMINI:Thank you, Dr. Blagg.

Dr.
Gillespie?

DR.
GILLESPIE:Yes.I think we have covered a lot of ground
today.And I think certainly I feel
like there is a lot of potential for this as being one modality among several
that we really need to move forward beyond the thrice weekly paradigm, which is
really more of a 1970s standard of care.

And
so whether it's nocturnal or short daily or peritoneal, there are a lot of
options.And this is one that we need
to look at.I think we certainly have
the technological ability to do it with the state of our technology today.

What
we really need now is the will to transform what our patients think, the
doctors, the dialysis companies, the manufacturers, everybody.There are a lot of different pieces to that
puzzle, but we certainly need to keep pressing on for that, anything we can do
to try to encourage more innovation in this, whether it's adapting existing
equipment to work more optimally for this or whether coming up with completely
new equipment is a goal we need to strive for.

CHAIRPERSON
TALAMINI:Thank you, Dr. Gillespie.

Dr.
Weinger?

DR.
WEINGER:Thank you.This is a very exciting opportunity for
society to really improve quality of life and potentially outcomes for patients
with a serious disease, but because we're talking about lay persons using a
potentially lethal device and process in their homes with limited or more
limited support, it really kicks it up a notch.

And
I feel that the FDA and the manufacturers, if for no other reason than for
their own self‑protection but regardless, need to look at these devices a
little more rigorously than existing in‑center devices.

That
doesn't mean that the FDA should stipulate how these things should be designed
but, rather, to ensure that the manufacturer has a rigorous design process,
which in this case particularly focuses on the human factors engineering
principles and includes, as specified in existing national and international
standards, key aspects of the design process, including a user‑centered
process; that is, patients and nephrologists are actively involved in the
design of the devices, that there is iterative design and evaluation, and that
there is functional; that is, performance‑based testing of the user
interface to assure that use errors are minimized.

In
addition, I think it's critical that both representative users and the use
environment be included in the evaluation, the design considerations and
evaluation, of these devices.And it
includes not just the design of the device but the training and labeling as
well.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Gibson?

DR.
GIBSON:As I have said before, I just
wanted to make a plea that there be no arbitrary exclusions based on
psychological criteria that centers, of course, have specific exclusions, much
like transplant programs do with regard to active substance abuse and unstable
mental illness.

And
even though I agree with the proposition that industry should not be charged
with proving this treatment is psychologically safe, I do think that if there
is a study, that it should be collected with regard to psychological effects
that occur, particularly on the family.

Whatever
labeling is decided upon, again, I just want to remind people that it should
take into account the cultural and ethnic diversity of the country that we live
in.

It's
my unfortunate duty to say that when I read through this, I noticed that we
were to talk about single needle devices, and I didn't hear that
mentioned.I suspect that could fall
under physician practice and using a single needle device with this, but I'll
just remind people that that was not mentioned in the discussion, even though
it was mentioned in the material.

CHAIRPERSON
TALAMINI:I would take the privilege of
the chair just for a moment.I run the
home TPN service at Hopkins.We had a
young woman who lost all of her bowels dependent on home TPN and had been quite
an outdoors woman.

She
called my office and asked if she could go camping on Assateague Island, wasn't
sure how that was going to happen.But,
in fact, she managed to do that.

She
took her cooler with her TPN and had it in the park ranger's tent.And every night, she would walk to the tent
and get her cold bag of TPN and infuse in her tent with her husband so that she
could have her camping experience.

So
I know that dialysis patients can't do that right now, but it certainly was
exciting for me to study these materials and to see the possibilities of
increased patient freedoms for this group of patients.

So
those are my only comments.Dr.
Aranoff?

DR.
ARANOFF:I agree with my colleagues
that dialysis is good and uremia is bad.And although nocturnal hemodialysis shares many aspects with current in‑center
and home dialysis therapies, it is fundamentally different in one way, and that
is that the treatment is provided by the patient while they are unconscious.

So
I think it is incumbent on this process through the FDA to assure that the
devices that are involved in this unique form of therapy have unique safety
precautions to provide these treatments in a safe and effective way.

CHAIRPERSON
TALAMINI:Thank you.

Dr.
Afifi?

DR.
AFIFI:I would like to make a comment
about the use of retrospective data to demonstrate substantial
equivalence.In principle, there is
nothing to prevent us from doing that.And if, indeed, someone comes in with a 510(k) application and can
demonstrate that there are existing data that could be used to show the
substantial equivalence, then all they have to do is demonstrate that, indeed,
they have the power in those data to be able to reject the null hypothesis of
equivalence against a specified alternative that the new device is so much
worse than the original device.So in principle,
I think we should not rule out historical data or retrospective data analysis.

CHAIRPERSON
TALAMINI:Thank you.

Dr.Sadler?

DR.
SADLER:I did not come here as an
advocate for nocturnal dialysis nor for in‑center dialysis nor for daily
dialysis or peritoneal dialysis.I come
as an advocate for patients.

I
think that all of these therapies are beneficial.We know that if we don't do any of them, the patients die.If we do one of them, the patients live.Depending on what we do and how we do it ‑‑
and it varies from one facility and one physician to the next ‑‑
the quality of the outcomes is different.

It
is very important that we focus on the patients and we try to do the best
job.I have serious concerns about the
nuisance value of dialyzing every day or five days a week.And I think that the optimal dialysis is
probably not the same for every patient and that we have not yet defined what
really should be considered optimal dialysis.

We
have certainly defined adequate dialysis in terms of something that avoids many
complications and keeps patients reasonably well but not really well.And we have enthusiasts who say that more is
better, and presumably there is no ceiling on that.I don't believe that either.

So
I think we have much to learn.And I
think that support of these efforts to use every modality that we can get to is
beneficial because it will give us more knowledge and we will learn where the
golden mean among these therapies is.

Having
said that, I'd like to say that I would agree with Rod Kenley that our
manufacturers have done a remarkable job.We have very good machines.They
may not be quite as elegant as Charlie Willock's first product in terms of the
ideas in it and the conservation of materials and energy, but they are
remarkably reliable, safe, much quieter, much more accurate, and they perform a
good service.

I
don't think that their performance is in question.And because of that, I don't think that we have a lot to
recommend to the FDA.And I believe
that if I were a manufacturer of one of these products, I would not come
forward and ask for another certification.

And
I'd be careful how I use my advertising, but I would point out to people what
my machine could do because I think all of them can do a lot.And I think that we need to be appreciative
of the information coming out of these trials so that we know what is best for
patients.

I
hope that Bob and Chris are correct that 20 percent of patients can do this,
but I'm skeptical.I think the number
may be closer to half that.But I think
that more people should do it.

I
do like home dialysis because of the convenience and flexibility it gives
patients, whatever kind of home dialysis they do.I don't believe that home dialysis just because it's at home is
better than because it's not at home, but the convenience and flexibility are a
great advantage.

I
think we have made some progress.We
have done a lot of conversation.And we
have reached a lot of agreement.I
think we have managed to demonstrate that whatever differences we had were far
smaller than our agreements. And I feel
pretty well fulfilled by what we accomplished today.

CHAIRPERSON
TALAMINI:Terrific.Thank you, Dr. Sadler.

Dr.
Duffell?

DR.
DUFFELL:Well, my compliments to the
chair.You ran a tight ship today, and
we kept moving.

CHAIRPERSON
TALAMINI:Thank you.

DR.
DUFFELL:So thank you for that.

My
closing comments are really more directed at FDA.Thank you for bringing this together.I think what I would like to ask of FDA is just that you all
quickly and efficiently pull this information together in industry.The toughest thing is not knowing, rather
than knowing, quite honestly.

So
even if we don't like what comes out of some of this today, I think at least
having it in a written format to start dealing with or to prepare cogent
arguments for another viewpoint is really what is important.

So
as quickly as you can summarize this and get out a guidance document, even in
the draft form, I think is going to be really helpful to everyone.

Thank
you for the opportunity to participate.

CHAIRPERSON
TALAMINI:Ms. Moore?

MS.
MOORE:I would like to thank you
professionals for tolerating and listening to a lay person.This has been a learning experience for me.

I
believe that the nocturnal home dialysis system is a positive and that if it
increases the quality of life for patients, if it increases their state of a
well‑being, I think then it is worthwhile.And I think that if we could get the technology to the point that
there won't be too many questions about it and that the users will be able to
handle it, then this will be a gift to society.

So,
therefore, I feel that with all that we have said here today and with FDA, in a
few years perhaps there will a few more lives saved.And that will be good.

CHAIRPERSON
TALAMINI:Thank you, Ms. Moore.

Ms.
Brogdon, does FDA have any further comments?

MS.
BROGDON:Yes.I just wanted to say a couple of things.I wanted to thank all of the panel members
for your preparation time and for your experience and the energy that you have
expended in this discussion today.

This
type of preliminary discussion for guidance development is typically very
difficult for panels to handle.And
sometimes we come away with not much to work with.I have to say in my many years at FDA, this is one of the best
preliminary discussions that I have heard.

So
our plan is to put together a draft in the next few months and send it out to
the public and to the panel members.It
would come up for further discussion at a panel meeting.

Also,
I just wanted to allay the fears as expressed earlier.This is not just an intellectual
exercise.We are getting these sorts of
requests from companies.And we do need
a guidance document, and this will help us develop that.

I
also wanted to say that we never forget that we have an obligation to regulate
in a least burdensome manner.And it's
least burdensome to all parties.And we
will try to keep that in mind as we draft the guidance document.

So
thank you all for your time.

CHAIRPERSON
TALAMINI:Thank you, Ms. Brogdon.

I
would, as the chair, like to also thank the panel.It's really pretty incredible to me the degree of expertise, the
set of pioneers that we have here, your ability to speak clearly and
succinctly, your obvious preparation before the meeting to be able to come and
crystalize these things quickly.So I
thank you very, very much.It's what
has made this really I think an excellent panel.

So
having said that, this concludes the report and recommendations of the
Gastroenterology and Urology Devices Panel on nocturnal home hemodialysis.And, again, on behalf of the FDA, I would
like to thank the entire panel.The
meeting is adjourned.